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NIA - National Institute on Aging

Project Summary Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 6.7 million people in the United States, yet the mechanisms underlying its pathology remain incompletely understood. In virtually every case of AD, extracellular amyloid-beta (Aβ) plaques and intracellular Tau neurofibrillary tangles co-occur, suggesting significant interplay between these two proteins. Although a direct link between Aβ plaque formation and Tau tangle deposition is still being elucidated, recent evidence indicates that soluble, intracellular Aβ oligomers can bind Tau and promote its aggregation. Both Aβ and Tau are intrinsically disordered proteins that undergo liquid– liquid phase separation (LLPS), forming protein-dense biomolecular condensates that can either facilitate physiological function or propagate pathological aggregation in neurons. Our preliminary data show that Tau condensates can adopt either a physiological state, recruiting tubulin to stabilize microtubules and resist aberrant aggregation, or a pathological one, where Aβ recruitment triggers fibril formation. Accordingly, we seek to characterize how Tau:Aβ interactions within condensates drive pathological aggregation, clarifying the kinetics of oligomeric species formation and identifying potential therapeutic targets. Additionally, we will determine whether reinforcing functional Tau:tubulin interactions can prevent or reverse the formation of pathogenic Tau:Aβ assemblies. In Aim 1, I will define how Aβ alters the structural properties of Tau condensates to drive pathological aggregation. Specifically, I will employ advanced biophysical techniques, including fluorescence lifetime imaging microscopy (FRET-FLIM) and microfluidic modulation infrared spectroscopy (MMS), to investigate whether Aβ accelerates Tau oligomerization within condensates and promotes β-sheet–rich, aggregation-prone structures. I will also delineate how these protein assemblies within condensates differ in kinetics and stability from analogous reactions occurring in dilute conditions. In Aim 2, I will determine whether tubulin can rescue Tau from this Aβ-driven pathology by reinforcing physiological Tau:tubulin interactions. Using an optogenetic system in neuronal cell lines, I will manipulate tubulin levels genetically and pharmacologically to test how tubulin enrichment affects Aβ-driven Tau aggregation, as measured by high-molecular-weight oligomers and hyperphosphorylated Tau. I will extend these findings to patient-derived induced pluripotent stem cell (iPSC) neurons to validate whether tubulin stabilization similarly protects against endogenous Tau pathology in a disease-relevant context. Upon completion of these studies, I will have established a mechanistic framework for how intracellular Aβ accelerates Tau aggregation via condensates, and how tubulin might mitigate this transition. These insights will contribute to our understanding of early-stage AD pathology and may inform future therapeutic strategies aimed at preserving or restoring physiological condensate function.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Synthetic Genetic Controller Circuits for Transcription Factor-Directed Differentiation PI: Domitilla Del Vecchio1,2,3 co-I: James J. Collins2,3,4,5 co-I: Thorsten Schlaeger6 1Department of Mechanical Engineering, MIT; 2Department of Biological Engineering, MIT 3Synthetic Biology Center, MIT; 4Broad Institute of MIT & Harvard; 5The Wyss Institute 6 Stem Cell Transplantation Program, Boston Children’s Hospital PROJECT SUMMARY The ultimate goal of this project is to create synthetic genetic circuits that accurately control the level of cell fate- specific transcription factors (TFs) autonomously in response to cell state changes. The underlying hypothesis is that the level and timing of expression of critical TFs dictates the efficiency of cell conversion protocols and the quality of produced cells. Here, we focus on the differentiation of human induced pluripotent stem cells (hiPSCs) into hemogenic endothelial cells (HECs) from which all hematopoietic stem and progenitor cells (HSC/HPCs) arise. Current methods to derive definite HECs (dHECs), which have the potential to produce adult-type lymphoid cells and HSCs, remain largely inefficient and are also difficult to execute and scale, and, as a consequence, exhibit high degrees of variability in out- comes between different labs, hiPSC lines, and even between replicate experiments.These problems hamper analysis of the underlying developmental processes and pose formidable obstacles to clinical translation of hiPSC-derived blood cell products since ensuring the safety and cost-effectiveness of the product necessitates high differentiation efficiency and consistency. Prior work has demonstrated that SCL (S), LMO2 (L), GATA2 (G), and ETV2 (E) TFs, when expressed in mesodermal cells, activate dHEC gene regulatory networks (GRNs) across species but also that efficient forward programming to dHECs requires discovery and subsequent implementation of both optimal expression levels and tim- ing for the TFs. Yet, conventional methods for TF-mediated cell fate programming generally rely on indiscriminate overexpression with little control on cellular TF levels and without cell state sensing. This is largely due to our inability to precisely control TF profiles during cell fate programming, and this limitation has prevented discovering optimal tra- jectories and subsequently enforcing them. Here, we propose synthetic genetic controller circuits that overcome this hurdle. In Aim 1, we create genetic circuit designs that set TF levels and use them in an efficient in vitro differentiation protocol to discover the optimal combination of S, L, G, E levels and timing. In Aim 2, we develop a circuit architecture, based on a novel TET1-enabled positive feedback system, to prevent epigenetic silencing of genetic circuits once de- livered to hiPSCs. In Aim 3, we make our genetic controller circuits enforce autonomously the optimal SLGE TF levels found in Aim 1 in response to the hiPSC-to-mesoderm transition. We achieve this by a new autocatalytic ADAR-based RNA sense-and-respond system, which senses the mesoderm marker Brachyury (TBXT) and enforces user-defined TF levels in response to it. We anticipate that this process, by being autonomous as opposed to manual and by enforcing optimal TF trajectories, will result in a more efficient, repeatable, and robust hiPSCs to dHECs conversion protocol, thereby helping fill the gap to clinical translation. Although in this project we tailor the genetic circuit designs to controlling SLGE TFs after sensing mesoderm-specific transcripts, the designs can be readily modified to express different TFs in response to any other cell type- or state-specific transcript. Therefore, we believe that the synthetic biology technology that we will establish will have broad impact on any other cell fate programming as well as on cell-or gene-therapy projects where expression levels and timing, as well as resistance to silencing, are important.

NHLBI - National Heart Lung and Blood Institute

Tachycardia, or abnormally fast heart rate, is an important risk factor for cardiovascular morbidity and mortality. Prolonged tachycardia is known to induce cardiomyopathy in patients who have no prior structural heart diseases. Moreover, transient tachycardia, frequently observed in heart failure patients, can exacerbate the cardiovascular outcome. However, very little is known about the molecular drivers underlying tachycardia-induced cardiac dysfunction. This gap in our knowledge hinders the development of more effective heart failure treatment, especially for patients with hard-to-control tachycardia. This K99/R00 proposal will leverage recent advances in induced pluripotent stem cell (iPSC), tissue engineering, and multiomics technologies to uncover the molecular signaling pathways critically involved in the pathology of tachycardia-related heart disease. The applicant, Dr. Chengyi Tu, has established and validated an in vitro tachycardia platform using engineered heart tissue (EHT). In Aim 1, Dr. Tu will perform metabolomic and transcriptomic profiling of EHTs with or without tachypacing. To validate the physiological relevance of the EHT model, canine samples from tachypacing-induced heart failure will also be profiled. Preliminary data from the EHTs and the canine samples coherently indicate that the disruption of glycolysis homeostasis may underly the impairment of cardiac function by tachycardia. Metabolomics analysis shows that tachypacing in EHTs resulted in a selective accumulation of glycolysis intermediates such as glyceraldehyde 3-phosphate (GA3P) and 3-phosphoglycerate (3PG). Interestingly, promotion of fatty acid metabolism accelerated the recovery of cardiac contractility in tachypaced EHTs. Based on these novel results, Aim 2 will focus on elucidating how different glycolysis intermediate metabolites affect the function of cardiomyocytes, which has yet to be systematically examined. Lastly, Aim 3 (R00 phase) will employ state-of-the-art mass spectrometry workflow to screen for novel binding targets of glycolysis intermediates in cardiac cells, and examine the potential therapeutic benefits of manipulating these targets. This K99/R00 proposal will be guided by an excellent mentoring team with diverse expertise, including mentor Dr. Joseph Wu (iPSCs and cardiac biology), co-mentor Dr. Sanjiv Narayan (arrhythmia), advisors Dr. Michael Snyder (genetics and multi-omics), Dr. Yuqin Dai (metabolomics), Dr. Stanley Qi (CRISPR interference) and Dr. Beth Pruitt (bioengineering), as well as collaborators Dr. Fabio Recchia (canine model) and Dr. Donald Bers (cardiac physiology). To sum up, the completion of the proposed study will significantly advance our mechanistic understanding of how tachycardia adversely affects the heart, thereby creating new opportunities for therapeutic interventions. The proposed training will significantly strengthen and expand Dr. Tu’s research expertise, providing substantial momentum to his transition toward an independent cardiovascular researcher.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. Our studies in humanized mice and non-human primates (NHPs) have demonstrated that hematopoietic stem cells (HSPCs) based CAR therapy could provide life-long engraftment and production of functional CAR-T, CAR-NK and CAR-Macrophages (CAR-M), resulting in significantly reduced viral rebound after ART withdrawal. These studies underscore both the feasibility and efficacy of HSPCs-based CAR therapy. However, major challenges remain to achieve sustained viral remission in the absence of ART with current engineered immunity approaches. Mounting evidence has shown that environmental factors, such as metabolic regulation, innate signaling and chronic inflammation greatly impact in vivo function and persistence of engineered immune cells. Here we propose to investigate pharmacological interventions to enhance metabolism of engineered cells, improve effector functions, reduce immune suppression, prevent/restore immune exhaustion, and enhance memory formation of engineered CAR cells in vivo. Building on our extensive work on CAR engineered immunity, innate signaling and immune metabolism, we will 1) improve CAR-MQ, CAR-T and CAR-NK effector function and enhance expansion of CAR T cells by modulate immune metabolism with lactase targeting enzymes; 2) promote CAR-T cell persistence, memory formation and prevent exhaustion by targeting mTOR (mammalian target of rapamycin) pathway; and 3) Optimizing CAR-cell function by temporal integration of metabolic and immunoregulatory modulators. To minimize off-target effects and toxicity, we will leverage our established nonocapsule platform to deliver these pharmacological modulators specifically to CAR-expressing cells. We hypothesize that targeted immune modulation will maximize the in vivo function and persistence of multilineage CAR cells, providing a robust strategy towards a functional HIV cure.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary / Abstract Type 1 Diabetes (T1D) results from progressive destruction of pancreatic β-cells driven by autoimmune attack and intrinsic stress. While much attention has focused on immune-mediated mechanisms, the contribution of β- cell–intrinsic stress pathways to disease progression remains incompletely understood. Emerging evidence implicates ChREBPβ (Carbohydrate-Responsive Element-Binding Protein β), a stress-inducible transcription factor, as a central integrator of metabolic and inflammatory signals that impair β-cell identity and survival. Although ChREBP has been studied in the context of glucose metabolism and Type 2 Diabetes, its pathological role in T1D remains unexplored. Our preliminary data demonstrate that ChREBP and its target genes are upregulated in β-cells from autoantibody-positive (AAb+) and T1D donors, as well as in NOD mice, suggesting early activation in disease pathogenesis. ChREBPβ overexpression induces apoptosis, oxidative stress, and β-cell dedifferentiation. We also developed a novel small molecule, Compound 43, which functions as a “molecular glue” that stabilizes the ChREBPα–14-3-3 interaction, thereby suppressing ChREBPβ expression and protecting β-cells from stress- induced damage, and we demonstrate here that this stabilizer is able to protect human β-cell identity and function under cytokine-induced toxicity. This proposal aims to define the contribution of ChREBPβ to β-cell dysfunction in T1D and evaluate the therapeutic potential of Compound 43 in mitigating this process. In Aim 1, we will characterize the impact of ChREBPβ activation on β-cell stress and survival under inflammatory and ER stress conditions using human islets. We will assess gene expression, apoptosis, UPR activation, and lipid metabolism using transcriptomic and lipidomic profiling. In Aim 2, we will test whether Compound 43 can protect human islets and stem cell– derived β-cells from cytokine- and ER stress–induced dysfunction, using functional, metabolic, and transcriptomic readouts. This study will establish ChREBPβ as a previously unrecognized contributor to early β-cell failure in T1D and provide preclinical validation for a new pharmacologic approach that targets β-cell resilience, rather than immune modulation. These findings will offer a new conceptual and therapeutic framework for preserving β-cell function in the earliest stages of T1D, directly aligning with the mission of the Human Islet Research Network (HIRN) to understand and prevent β-cell failure.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Dilated cardiomyopathy (DCM) is one of the most common hereditary heart conditions, yet effective targeted therapies remain lacking. Extensive myocardial fibrosis underscores the critical role of non-myocyte dysfunction, particularly fibroblasts, in disease progression. Concurrently, immune activation and macrophage infiltration are increasingly recognized in DCM, implicating inflammation as a key driver of adverse remodeling. However, the mechanisms by which inflammatory signals activate fibroblasts remain poorly defined. This multi-PI R01 integrates patient-specific induced pluripotent stem cells (iPSCs), 3D cardiac organoids embedded in engineered disease-specific niches, CRISPR-based high-throughput screening, single-cell RNA sequencing (scRNA-seq), bioinformatics, and in vivo DCM mouse models to investigate and therapeutically target this axis. In Aim 1, we will test how inflammatory signals from DCM iPSC-derived cardiomyocytes (iPSC-CMs) initiate tri-cellular crosstalk with macrophages (iPSC-MΦs) and fibroblasts (iPSC-CFs), promoting fibroblast activation through key signaling and feedback loops. In Aim 2, we will evaluate how immune–fibroblast crosstalk contributes to fibrotic remodeling and cardiomyocyte dysfunction using single-cell, monolayer co-culture, and 3D cardiac organoid platforms embedded within engineered fibrotic niches. In Aim 3, we will map immune–fibrotic networks using scRNA-seq and genome-scale CRISPRi/a screens, followed by high-throughput drug screening and validation of prioritized targets, in both iPSC-based systems and in vivo DCM mouse models. Together, this study will define the cellular and molecular mechanisms of immune–fibroblast crosstalk in genetic DCM and accelerate the development of precision antifibrotic therapies.

NIA - National Institute on Aging

Aging with co-morbid conditions (i.e., obesity, hypertension) increases the risk of developing heart failure with preserved ejection fraction (HFpEF), and related cardiovascular morbidity and mortality for which there are few approved treatments. Importantly, HFpEF has become the most common form of HF and is characterized, in part, by cardiac fibrosis and reduced capillary density (i.e., rarefaction). Capillary rarefaction is associated with cardiac fibrosis in HFpEF and cardiac fibrosis is independently predictive of cardiac mortality in adults >70 years of age. LARP6 (La Ribonucleoprotein 6, Translational Regulator), an RNA binding protein, is implicated in pathologic fibrosis via binding to a unique 5' stem loop (5'SL) structure in collagen mRNA resulting in mRNA stabilization and increased translation, and excess collagen production/deposition. Our preliminary data provide the first evidence of LARP6-dependent cardiac fibrosis and dysfunction in response to chronic cardiac stress. Specifically, disruption of the LARP6-collagen mRNA interaction in a genetic (unique knock-in mouse model where the 5'SL region is mutated to prevent LARP6 binding; 5'SL mutant mice) and an interventional (the use of C9, a small molecule inhibitor of LARP6-collagen mRNA interaction) model each prevented cardiac fibrosis and contractile dysfunction following chronic β-adrenergic stimulation. Moreover, disruption of LARP6- collagen interaction promotes pro-angiogenic LARP6 signaling exhibited by increased capillary density and vasculogenic gene signatures in the heart. Lastly, cardiac LARP6 expression is increased in aging. Based on these `proof of concept' findings, we hypothesize that LARP6 signaling is a druggable target for the treatment of co-morbid aging-associated HFpEF. To test this hypothesis, we will utilize a `three-hit' mouse model of co- morbid aging-associated HFpEF to examine the following Specific Aims: Aim 1 will delineate the therapeutic potential of targeting LARP6-collagen interaction in cardiac fibrosis and dysfunction in lean and HFpEF 5'SL mutant mice/littermate controls (genetic) as well as lean and HFpEF C57BL/6J mice treated with C9 or vehicle (interventional). Cardiac morphology, function, and fibrosis in vivo by magnetic resonance imaging coupled with ex vivo analysis of fibrosis by staining and atomic force microscopy and assessment of LARP6 signaling will serve as major endpoints. Utilizing the same genetic and interventional models (5'SL mutant mice and C9), Aim 2 will elucidate the therapeutic potential of LARP6-Vegfa manipulation on capillary rarefaction and cardiac vasculogenic signaling in co-morbid aging-associated HFpEF. Capillary density, cardiac vascularity, analysis of cardiac pro-angiogenic mediator expression, delineation of the cardiac myocyte and non-myocyte transcriptome, and capillary sprouting in a tissue culture model are major endpoints. Together, the proposed conceptually innovative and translationally significant studies will provide novel evidence that disruption of LARP6-collagen interaction is a viable therapeutic target to attenuate cardiac fibrosis and enhance vascularity in co-morbid aging-associated HFpEF for which there are currently few approved treatments.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease that destroys insulin-producing beta cells in the pancreas, requiring insulin injections and blood glucose monitoring, which do not replicate the precise glycemic control of functional beta cells nor prevent disease progression and complications. In long-standing T1D, most beta cells are destroyed, which requires the replenishment of beta cell mass to restore insulin production. This can be achieved by regenerating endogenous beta cells or differentiating human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) into beta cells for transplantation, combined with therapies to prevent autoimmune destruction of the newly formed beta cells. Different therapeutic windows exist for intervention or a potential cure, particularly in early-onset or newly diagnosed T1D where significant beta cells remain, presenting an opportunity to intervene and preserve these cells, potentially delaying or preventing further beta cell loss. Recent findings suggest that beta cell injury or stress may significantly contribute to immune- mediated beta cell loss in T1D, thus therapies aimed at reducing beta cell stress and injury may avert immune targeting during the progression to overt T1D. Combining beta cell therapies with immune modulation may yield better outcomes, yet the specific targets and pathways for effective treatment remain unclear. Renalase (RNLS) has emerged as a promising therapeutic target in T1D, being associated with T1D in genome-wide association studies (GWAS) and linked to beta cell protection. Loss of RNLS function in beta cells reduces endoplasmic reticulum (ER) and oxidative stress, immune cell infiltration, and natural killer (NK) cell activation, preventing autoimmune destruction. Designing a better strategy for targeting RNLS enzymatic activity may offer a potential therapeutic strategy for T1D by providing beta cell protection against stress and autoimmunity in humans. RNLS, known as an oxidase similar to monoamine oxidases (MAO), can be bound by some MAO inhibitors. We found that one of the FDA approved MAO inhibitors, Pargyline, is able to bind to RNLS and protect pancreatic beta cells from stress and autoimmune destruction. Apparently, pargyline may not be specific or potent enough for RNLS. Therefore, developing a more specific and potent RNLS inhibitor is crucial. Utilizing structure-based drug design, the goal is to create a new class of compounds for early or preventive treatment of T1D. This research includes uncovering RNLS's role in beta cell metabolism and immune interactions, characterizing RNLS structure and enzymatic function for robust assay development, and evaluating RNLS inhibitors by biochemical, cell, and animal model-based assays. The expected outcome is the development of potent and selective RNLS inhibitors that enhance beta cell survival and function, reduce stress and autoimmune destruction, and demonstrate safety and efficacy in humanized mouse models, providing promising therapeutic options for T1D by protecting beta cells from stress and immune attacks at an early stage.

NEI - National Eye Institute

Project Summary Mitochondria play a crucial role in maintaining neuronal health and function. Dysfunction of these organelles leads to various neurological diseases. Retinal ganglion cells (RGCs), the primary output neurons in the retina, are particularly vulnerable to mitochondrial damage. The two most common hereditary optic neuropathies characterized by RGC degeneration, Autosomal Dominant Optic Atrophy (ADOA) and Leber Hereditary Optic Neuropathy (LHON), both stem from mitochondrial dysfunctions. ADOA arises from mutations in OPA1, which regulates inner mitochondrial membrane fusion, while LHON is caused by mutations in the complex I subunit genes encoded by the mitochondrial genome. Currently, no effective treatments exist for either condition, underscoring a critical unmet need to unravel the disease mechanisms and develop therapies to safeguard RGCs from degeneration. The project’s significance lies in investigating the role of SARM1, a trigger of neurodegeneration, in mitochondria-induced RGC degeneration. Our lab has built a novel ADOA mouse model carrying the pathogenic Opa1R290Q/+ mutation. This model recapitulates key features of human ADOA, including mitochondrial fragmentation, aberrant glutathione redox, age-related RGC degeneration, and declines in RGC function. We found that knocking out Sarm1 in these ADOA mice nearly completely protects against all the degenerative phenotypes, suggesting that SARM1 activation drives RGC death in ADOA. Given the similarities between ADOA and LHON, we hypothesize that the same mitochondria-SARM1 pathway also contributes to LHON pathology. Therefore, the central hypothesis of the project posits that mitochondria-induced SARM1 activation leads to RGC death in both ADOA and LHON, and inhibiting SARM1 represents a promising therapeutic approach. Aim 1 of the proposal aims to identify specific mitochondrial defects triggering SARM1 activation in OPA1 mutant RGCs, and elucidate the underlying mechanisms. Aim 2 seeks to establish a dominant-negative SARM1-based therapeutic approach in ADOA mice. During the R00 phase in Aim 3, I will characterize a LHON mouse model and examine whether Sarm1 KO provides protective effects. I have assembled an advisory committee to provide conceptual and technical guidance as I pursue this study. Furthermore, I have also formulated a comprehensive training and career development plan to be executed during the grant period. This integrated proposal, encompassing the research plan and mentoring activities, will provide me with a solid foundation to embark on an independent academic career.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Hashimoto’s Thyroiditis (HT) is a prevalent autoimmune disease affecting 15% of the population and characterized by chronic autoimmune attack on thyroid follicular cells. Over time, this persistent autoimmune attack results in thyroid gland failure and the requirement for lifelong hormone replacement, a hallmark shared with other chronic autoimmune diseases such as Type 1 Diabetes Mellitus (T1DM) and Addison’s Disease. Despite its prevalence, the mechanisms driving the unrelenting autoimmune attack in HT remain poorly understood. Identifying factors underlying the persistent autoimmune response, may identify new therapeutic targets to halt disease progression in HT and similar chronic autoimmune disorders. We have identified a population of TCF7+ stem-like progenitor CD8 T cells within the thyroid tissue of HT patients, analogous to those seen in chronic viral infections and Type 1 Diabetes, that sustain autoimmune attack by replenishing the pool of terminally differentiated cytotoxic effectors. Using single cell RNAseq and TCRseq of human thyroid specimens from individuals with HT, our preliminary data further demonstrate the transcriptional transition and clonal expansion of TCF7+ progenitor CD8 T cell to effectors with killing ability within the thyroid. In addition, our preliminary data suggest that tertiary lymphoid structures (TLSs), organized collection of immune cells within the thyroid, provide a microenvironment that promotes autoimmunity, driven in part by CD4 T follicular helper (Tfh) cells and IL-21, a cytokine implicated in CD8 T cell differentiation. Using a mouse model of HT, we demonstrate that IL-21R deletion protects against thyroid autoimmunity, suggesting that TLS-associated factors may drive the conversion of progenitor CD8 T cells into cytotoxic effectors. Thus, our overarching hypothesis is that TCF7+ CD8 T progenitor cells sustain autoimmune persistence in HT, while TLS- associated signals promote their differentiation into cytotoxic effectors, perpetuating disease progression. In Aim 1, we will define the role of TCF7 in maintaining stem-like CD8 T cells by genetically deleting TCF7 in an HT mouse model and using WNT pathway agonists to assess its regulatory function. In Aim 2, we will investigate TLS-driven CD8 T cell conversion by assessing the deletion of CD4 Tfh cells and IL- 21 signaling in HT progression using mouse models. We will leverage spatial transcriptomics data previously collected by our lab from HT thyroid specimens, to determine how TLS localization influences CD8 T cell differentiation. These studies will uncover fundamental mechanisms of chronic autoimmunity in HT, providing potential therapeutic targets to disrupt persistent autoimmune attack and yielding broader insights into T cell– mediated autoimmune diseases.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary: PFA ependymoma is a rare and aggressive pediatric brain tumor with a poorly understood molecular mechanism. Unlike many cancers, PFA ependymoma exhibits very few genetic alterations. Instead, it is thought to be driven primarily by epigenetic dysregulation. A key player in this disease is the EZH1/2 inhibitory protein EZHIP, which is normally expressed only in germ cells. EZHIP is aberrantly expressed in PFA ependymoma, where it disrupts the function of Polycomb Repressive Complex 2 (PRC2), a master epigenetic regulator of developmental gene repression through deposition of the trimethylated histone H3 lysine 27 (H3K27me3) repressive histone mark. EZHIP-mediated dysregulation of PRC2 involves both enzymatic inhibition and physical stalling of PRC2 on CpG island (CGI) chromatin, leading to a global loss of H3K27me3 levels, an epigenetic hallmark of PFA ependymoma. PRC2 itself is a highly dynamic and intricate complex that assembles into two functional variants, PRC2.1 and PRC2.2. These two variants share a core composed of the catalytic subunits EZH1/2, along with EED, SUZ12, and RBBP4/7, and differ by incorporating distinct accessory subunits. PRC2.1 includes PHF1/MTF2/PHF19, EPOP, and PALI1/2, while PRC2.2 features AEBP2 and JARID2. Our preliminary data reveal intriguing molecular crosstalk between EZHIP and multiple PRC2 components, suggesting potential competitive or cooperative interplay. The ability of EZHIP to inhibit PRC2 partly stems from its mimicry of the oncohistone H3K27M, which harbors a lysine-to-methionine mutation that causes diffuse midline glioma, another devastating brain tumor in children, where PRC2 activity is also globally suppressed. However, the precise, EZHIP-specific mechanisms behind PRC2 dysregulation in PFA ependymoma remain largely unexplored. Our work aims to uncover these elusive mechanisms using a powerful combination of structural biology, biochemistry, and genomics approaches. Ultimately, we aim to identify therapeutic strategies that disrupt the pathogenic EZHIP–PRC2 crosstalk and restore the normal H3K27me3 epigenetic landscape. Specifically, in Aim 1, we will determine the structural and biochemical mechanisms underlying the enzymatic inhibition of the PRC2 core complex by EZHIP. In Aim 2, we will elucidate the molecular basis of EZHIP-mediated stalling of PRC2 on CGI chromatin, involving PRC2 functional variants. In Aim 3, we will explore an exciting mechanism-based therapeutic strategy to overcome PRC2 enzymatic inhibition and chromatin stalling induced by EZHIP.

NHLBI - National Heart Lung and Blood Institute

Project Summary Dilated cardiomyopathy (DCM) is a common cause of heart failure with a severe lack of therapeutics, creating a significant clinical burden. The gene TRAPPC11 emerged from a whole transcriptome, functional screen for therapeutic targets for DCM using patient-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), demonstrating reversion of contractile dysfunction upon knockdown in DCM hiPSC-CMs. TRAPPC11 is a modulator of endoplasmic reticulum (ER) stress. Since ER stress is recognized as a pathophysiological driver in DCM, my overarching hypothesis is that inhibition of TRAPPC11 would be therapeutic for DCM caused by TNNT2 mutations and possibly more broadly for other forms of DCM. This hypothesis will be tested through knockdown of TRAPPC11 in a mouse model of TNNT2 DCM and in myofilament and nonmyofilament induced DCM in hiPSC-CMs. Interestingly, single nucleotide polymorphisms (SNPs) in TRAPPC11 are associated with left ventricular hypertrophy (LVH) in response to pressure overload in African Americans. Therefore, my secondary hypothesis is that common mechanisms underlie TRAPPC11’s effect on hypertrophy induction and its therapeutic potential for DCM. Using CRISPR/Cas9 genome editing, I will test the effects of TRAPPC11 SNPs associated with LVH on ER/SR function in healthy hiPSC-CMs and introduce key SNPs into DCM hiPSC-CMs to assess their protective potential. Completion of this study will establish a translational and mechanistic rationale for targeting TRAPPC11 in DCM, and might warrant monitoring clinical outcomes of people carrying these SNPs for evidence supporting translatability of targeting TRAPPC11 to treat DCM. The training program proposed in this fellowship application was created to support my potential to become an independent investigator in the future. It will take place in the highly supportive, rich academic environment of Stanford University, where I will have access to state-of-the-art facilities and the opportunity to interact with leading cardiovascular researchers. The plan encompasses scientific technical skills, professional development skills, and both written and oral communication skills and will prepare me for writing my career development award.

NCATS - National Center for Advancing Translational Sciences

SUMMARY Adaptor proteins that function exclusively through protein–protein interactions (PPIs) comprise one of the largest classes of undruggable targets. SMAD4, the central adaptor in the canonical TGF-β signaling pathway, exemplifies this challenge. Germline mutations in SMAD4 cause Myhre Syndrome (MS), a rare autosomal dominant multisystem disorder characterized by severe fibrosis, vascular stenosis, restrictive cardiomyopathy, and respiratory complications. Our recent studies identified SMAD4-I500V as a gain-of-function mutation that drives a hypermorphic SMAD4–SMAD3 interaction (hyperPPI), leading to excessive TGF-β signaling output. This discovery establishes a new paradigm in Myhre biology, in which hyperPPIs can function as pathogenic drivers and potential therapeutic targets. However, no physiologically relevant platforms currently exist to interrogate SMAD4-I500V hyperPPI in the patient context or to discover small-molecule modulators that could normalize this signaling axis. This proposal will establish two complementary, patient-derived experimental systems that together address this critical gap. In Aim 1, we will develop the Myhre iPSC hyperPPI Biosensor System (MiBS) by CRISPR-engineering Myhre patient–derived and sibling control induced pluripotent stem cells (iPSCs) with live-cell biosensors for allele-specific monitoring of SMAD4-I500V/SMAD3 hyperPPI. MiBS will enable multiplexed, quantitative, and high-throughput detection of pathogenic SMAD4 interactions in their native genomic and cellular context, providing an unprecedented platform for chemical screening and mechanistic dissection. In Aim 2, we will establish the Cardiac Organoid Phenotyping System (CoPS) by differentiating Myhre and control iPSCs into multicellular 3D cardiac organoids that recapitulate cardiomyocyte, fibroblast, and endothelial interplay. CoPS will be used to define functional disease phenotypes—including contractility, calcium handling, and electrophysiology—as well as molecular signatures of fibrosis, vascular integrity, and cardiomyocyte maturation. Single-cell transcriptomic profiling will further resolve lineage-specific alterations and disrupted intercellular communication networks. By integrating MiBS and CoPS, this project will generate the first physiologically and mechanistically relevant platforms to model SMAD4-I500V hyperPPI in Myhre Syndrome. These tools will illuminate how undruggable adaptor proteins drive rare disease, while establishing scalable, HTS-compatible systems for future therapeutic discovery. More broadly, the approaches developed here are generalizable to other adaptor proteins and PPI-driven pathologies, offering a conceptual and experimental framework for expanding the target landscape to previously intractable biology.

NINDS - National Institute of Neurological Disorders and Stroke

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective treatment. Among the identified ALS-causing genes, several encode RNA binding proteins including FUsed in Sarcoma (FUS). Mutant FUS protein is mis-localized to the cytoplasm where it forms inclusions, a pathological hallmark of ALS. We and others have studied the FUS protein under physiological and pathological conditions in various models. Notably, we recently identified six individuals in an extended ALS kindred who carry the ALS-linked FUS R521G mutation but remain free of ALS well into their 60s and beyond (Unaffected Mutation Carriers, UMCs). We generated induced pluripotent stem cell (iPSC) lines from four UMCs, six FUS ALS patients, and four healthy controls, differentiated them to motor neurons (iMNs), and measured their electrophysiological properties. FUS ALS iMNs demonstrated disease-related hyperexcitability, whereas UMC and control iMNs displayed normal electrophysiological properties. Using an integrated analysis of whole genome sequencing and RNA-Seq data, we identified a cluster of variants in the 3’ untranslated region (3’-UTR) of the microtubule- associated protein tau (MAPT) gene. This set of linked variants was highly expressed in all UMCs but was absent in all ALS patients. More excitingly, an isogenic line with these variants incorporated into MAPT 3’-UTR of an ALS iPSC showed normal electrophysiological properties, supporting that these variants are critical to mitigating the hyperexcitability phenotype. iMNs from FUS ALS patients had increased Tau protein levels as compared to those from UMCs with the MAPT variants. In addition, overexpression of Tau induced neuronal hyperexcitability whereas Tau knockdown restored neuronal excitability to normal. We thus hypothesize that the MAPT variants reduce Tau protein expression, mitigate iMN hyperexcitability, and ultimately protect UMCs from developing ALS. Three specific aims are designed to test the hypothesis. Aim 1 is to establish the causative role of the MAPT 3’-UTR variants in reducing the hyperexcitability phenotype. We will generate additional isogenic lines by introducing the wild-type MAPT allele to UMC iPSCs to solidify the causative role of the MAPT variants in determining ALS or UMC phenotypes. We will generate and characterize two isogenic lines carrying 4 rare variants or 10 common variants to delineate their contributions. Aim 2 is to determine how the FUS mutation increases Tau expression and alters other properties, and how the MAPT variants prevent these abnormalities. Aim 3 is to determine which ion channel or receptor is responsible for the ALS-related hyperexcitability phenotype, and to examine whether up- and down-regulation of Tau expression changes the specific ion channel or receptor activity. The proposed studies are highly innovative conceptually and technically. The results will provide insights into the mechanisms underlying the protective effects of the MAPT variants and identify potential novel therapeutic targets. This project has a broader impact beyond ALS since Tau plays a critical role in other neurodegenerative diseases.

NASA Johnson Space Center

The National Aeronautics and Space Administration (NASA), Johnson Space Center (JSC), Office of Education (OE), is releasing a Cooperative Agreement Notice (NNJ08237878C) for submission of proposals to support the administration and activities of Teaching From Space (TFS). TFS is a NASA Education office co-located with the Astronaut Office at Johnson Space Center (JSC). As part of the FY2006 realignment of NASA Education projects from NASA Headquarters to NASA Field Centers, management of the Educator Astronaut Project (EAP) and Education Flight Projects (EFP) and their associated activities transitioned to the JSC Education Office and were integrated with TFS. JSC is the Lead Center for the projects and other NASA Field Centers and JPL are involved in the implementation of project activities. The JSC Education Office has a single project manager for TFS activities. EAP/EFP and other TFS activities offer NASA Education unique capabilities and opportunities to involve educators and students through astronaut training, spaceflight missions, on-orbit education activities, future flight platforms and space missions, and a variety of education flight projects. All TFS activities are designed to support an integrated vision and objectives. The vision for TFS is: Facilitate education opportunities that use the unique environment of spaceflight and other flight platforms. TFS will focus its efforts to meet three objectives: 1. Develop and provide NASA-unique experiences, opportunities, content, and resources to educators and students to increase K-12 student interest in STEM disciplines. 2. Develop and facilitate a NEAT-like (Network of Educator Astronaut Teachers) group of highly motivated educators. 3. Build internal and external partnerships with formal and informal education communities to create unique learning opportunities and professional development experiences. Institutions eligible to respond to this CAN are limited to higher education institutions, nonprofit organizations, or consortia of organizations and institutions serving higher education. Upon it's release date, this CAN will be available electronically through http://www.grants.gov/. Electronically submitted Notices of Intent to propose are requested. Proposal due date is April 28, 2008. The electronic submission of each proposal's Cover Page/Proposal Summary/Budget Summary is required by the due date for proposal submission. This solicitation leading to the award of a Cooperative Agreement is issued pursuant to title 14 CFR Part 1260 for educational and nonprofit institutions and 14 CFR part 1274 for commercial organizations. Notwithstanding the posting of this opportunity at FedBizOpps.gov, Grants.gov, or at both sites, NASA reserves the right to determine the appropriate award instrument for each proposal selected pursuant to this announcement. Direct questions specifically regarding this solicitation to: Edward J. Pritchard, Project Manager, edward.j.pritchard@nasa.gov or Cynthia McArthur, Project Lead, Cynthia.1.mcarthur@nasa.gov.

NIGMS - National Institute of General Medical Sciences

How do cells in mammalian organisms integrate various inputs to generate elaborate spatial arrangement of differentiated cell types as seen in tissues and organs? Naturally evolved genetic networks based on ligands and receptors are essential for embryonic development and maintaining adult tissues. Alterations in genes, effector proteins, and cellular environments can disrupt normal development, leading to congenital disorders and adult diseases such as cancer and degeneration. Recently, synthetic genetic networks based on synthetic receptors have been developed and used in research settings to perturb and reconstruct complex multicellular networks (e.g., synNotch receptors that we developed). In our lab, we have two main goals: to develop new technologies to manipulate cell differentiation in space and time with synthetic signaling systems, and to apply these technologies to reconstruct specific examples of complex arrangement of cells, for example here a multilayered arterial vessel. In the Research Strategy section of this proposal, we outline two research Tracks, and their respective goals: 1. Development of New Technologies for 3D Differentiation Control: We will develop and integrate two technologies: (i) control of differentiation in three dimensions (3D) layers of defined thickness around spherical or thread-like scaffolds to model organs with radial symmetry around a nucleus like liver, branched epithelia, skin, and blood vessels among others; (ii) autonomously patterning genetic circuits of the reaction-diffusion family to obtain 2D and 3D gene expression domains like spots, stripes and labyrinth, known as Turing-like patterns. 2. Study and control of cell-cell communication among differentiating endothelial and vascular support cells: we will utilize patterned Syn-Notch signaling to build a perfusable vasculature comprised of an endothelial intima and a smooth muscle media layer of controlled thickness. We will generate and perturb these constructs where human induced pluripotent stem cells are differentiating to endothelial cells and vascular smooth muscle cells in geometrically controlled fashion in 2D and in 3D. We will identify and use the signals and communication network that support construction of perfusable functional tissues. These studies aim to enhance synthetic and developmental biology by deepening our understanding of cell signaling mechanisms in multicellular communities. Ultimately, these insights could advance cell-based therapies and improve disease treatment strategies.

OD - NIH Office of the Director

Abstract Musculoskeletal (MSK) disorders affect approximately 126.6 million adults in the United States, accounting for more than half of the adult population. The development of disease-modifying drugs (DMDs) for these conditions remains particularly challenging due to subjective clinical assessments, the absence of reliable animal models that closely mimic human pathology, and the high costs associated with large-animal studies. MSK disorders are influenced by various factors, including environmental exposures, aging, hormonal changes, degenerative diseases, and injuries, impacting individuals across all demographics. While surgical interventions are sometimes an option, they often have high failure rates, leading to disability and progressive tissue deterioration. The financial burden is immense, with U.S. healthcare costs related to MSK conditions exceeding $400 billion annually. To overcome these challenges, innovative preclinical platforms incorporating human cells and tissues are crucial for generating reliable data to support DMD development. Our team consists of experts with a strong track record in bioengineered systems that accurately replicate human MSK structures and functions. Leveraging our extensive experience with stem cells, organoids, and advanced in vitro culture platforms, we propose the establishment of an MSK New Approach Methodologies (NAMs)Technical Development Center (TDC) to drive the innovation of combinatory physiological models for muscle, cartilage, tendon, and intervertebral disc research. Through this initiative, we will investigate MSK pathologies—including mechanical overloading, inflammation, and injury—while considering key influences such as environmental exposures, aging, and hormonal effects. Additionally, by collaborating closely with the Consortium Steering Committee, the Validation and Qualification Network (VQN), and the NAMs Data Hub and Coordinating Center (NDHCC), the MSK NAMs developed through this effort will be widely accessible to a broad range of downstream users.

NIA - National Institute on Aging

Abstract Telomere entanglements: formation, disentanglement, and impact of failed disentanglement on genome stability To preserve genome stability, replicated sister chromatids must be disentangled and cleanly separated at mitosis. Telomeres safeguard this process by protecting chromosome ends from degradation and end-joining reactions that generate dicentric chromosomes and rampant chromosome instability. In most human somatic cells, however, telomerase is inactive, leading to progressive telomere erosion over time. This raises a fundamental question: what protective functions are lost as telomeres shorten and become dysfunctional? Telomeres are well known for preventing end fusions, but we have uncovered an additional threat: telomere entanglements. These arise when stalled replication forks at dysfunctional telomeres fail to restart and engage in aberrant interactions, leading to persistent DNA bridges during mitosis. The fission yeast telomere-binding protein Taz1, and its mammalian ortholog TRF1, promote replication fork progression through telomeres and prevent such entanglements. Loss of Taz1 causes stalled telomeric forks that generate anaphase-spanning DNA bridges. We find that resolution of these structures depends on the timing of anaphase midregion nuclear envelope breakdown, which exposes the entanglements to the cytoplasm, an unexpected but essential step for entanglement resolution. This proposal dissects the mechanisms governing telomere entanglement formation and resolution. We hypothesize that the most problematic entanglements stem from strand invasions between stalled forks on different chromosomes, forming non-sister telomere entanglements. We will define their molecular structure and investigate how long noncoding telomeric RNAs and RecQ helicases contribute to their formation. We further show that resolution involves a noncanonical function of Topoisomerase II, likely modulated by the condensation state of Top2- DNA complexes, a novel concept with broad implications. While these discoveries emerged from studies in S. pombe, our preliminary findings reveal similar entanglement phenotypes in mammalian cells, particularly in response to telomeric replication stress. We will extend these studies to human cells undergoing telomere-driven replicative aging, to assess whether telomere entanglements contribute to the genomic instability associated with aging. Together, this work defines a previously unrecognized consequence of telomere dysfunction and illuminates the molecular handoff between stalled replication and chromosome segregation at the critical final act of mitosis, the moment of truth when euploidy is either preserved or lost.

Tennessee Department of Education

STEM education initiative grants for TN to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY/ABSTRACT Hereditary Spastic Paraplegia 4 (SPG4-HSP) is an underdiagnosed neurodegenerative disorder characterized by progressive weakness and spasticity in both legs that escalate into wheelchair dependence. Symptoms result mainly from dying-back degeneration of corticospinal tracts. The disease is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Recent studies indicate that that disease pathology is primarily driven by the M1 isoform of spastin, which, when mutated, becomes toxic. A logical therapeutic strategy would be to reduce mutant M1 levels and restore axonal integrity, with the goal of halting and potentially reversing disease progression. Mutant M1 becomes not only toxic but also resistant to degradation, causing it to accumulate. A multi-PI team at Drexel University has developed three recombinant monoclonal antibodies with high specificity for M1. These antibodies were then engineered into intrabody vectors encoding their variable regions for intracellular expression in affected neurons. These intrabodies include a lysosome-targeting sequence to direct the antibody–antigen complex for degradation. This strategy, previously validated for other mutant proteins, is well-suited for SPG4-HSP and could represent a breakthrough therapy. Key questions remain: Can mutant M1 be effectively and sustainably depleted without off-target toxicity? If wildtype M1 is also affected, can any ill effects of this be mitigated? The multi-PI team has developed human induced pluripotent stem cell (hiPSC)-based platforms for studying SPG4-HSP. To test the intrabody approach, the multi-PI team has developed two isogenic hiPSC lines, each with a distinct SPAST mutations, and five SPG4-HSP patient-derived hiPSC lines with their mutation-negative familial controls. These cells are differentiated into motor cortical organoids (MCOs), which are forebrain organoids enriched for corticospinal motor neurons, the neuronal population most affected in SPG4-HSP. Across diverse mutations, MCOs consistently recapitulate disease-relevant phenotypes, including elevated HDAC6 activity, reduced microtubule acetylation, and enhanced neurodegenerative phenotypes. By introducing intrabody vectors into MCOs, it will be determined whether degrading mutant M1 restores cellular homeostasis and reverses neurodegeneration. By integrating precision intrabody engineering with patient-specific hiPSC-derived MCOs, this proposal seeks to mechanistically validate and therapeutically correct the pathogenic accumulation of mutant M1, establishing a novel, targeted approach with strong potential for clinical translation in SPG4-HSP treatment.

NHLBI - National Heart Lung and Blood Institute

Project Summary Sickle cell disease (SCD) is an inherited hemolytic anemia that afflicts 100,000 patients in the United States and millions worldwide. Those with SCD suffer from recurrent pain, ischemia-perfusion injury, chronic inflammation, progressive organ damage and a shortened life and healthspan. SCD epitomizes chronic hematologic stress in the form of bone marrow (BM) inflammation, increased hematopoietic demand, and BM niche damage, which can damage and deplete BM hematopoietic stem and progenitor cells (HSPCs). Evidence is building that the pathologic stress of SCD selects for mutant HSPCs that put patients at risk for additional hematologic disease, especially when subject to stressors such as exposure to cytotoxic chemotherapy prior to hematopoietic cell transplant (HCT) or during gene therapy. As these are the only potentially curative therapies for SCD, it is important to better understand and prevent SCD-induced insults to HSPCs. We found that BM HSPCs from mice and SCD individuals contain DNA damage, oxidative stress, and precocious senescence. These phenotypes correlated with a severe loss of blood repopulating and hematopoietic colony activity from the BM of mice and individuals with SCD, respectively, that inversely correlated with high expression of molecular enforcers of senescence. We demonstrated that treatment of SCD mice with the senescence targeting therapy (STT), navitoclax (ABT-263), reduced numbers of HSPCs with DNA damage and restored hematopoietic repopulating activity to the BM. Thus, STTs have the potential to rejuvenate damaged BM HSPCs for downstream applications in hematopoietic cell transplant and gene therapy in SCD. Here, we propose to build on these promising ‘proof of principle’ studies and establish the pre-clinical rationale for STTs to improve HSPC function and numbers during SCD. As navitoclax causes dose-limiting cytopenias and is not FDA approved, in Aim 1 we will employ a pre-clinical SCD mouse model and BM HSPCs from individuals with SCD to interrogate the ability of FDA-approved STTs to restore function to BM HSPCs during SCD. We will also define the therapeutic window of STTs in our pre-clinical SCD model. In Aim 2, we will test our hypothesis that STTs can improve the mobilization of high-quality HSPCs during SCD following treatment with the CXCR4 antagonist, plerixafor, using a pre-clinical model of SCD. We will also test mobilized cells for gene editing efficiency in furtherance of translating this work to our ongoing clinical trial for gene editing-based autologous therapy for SCD (SAGES1, NCT06506461). In Aim 3, we will interrogate the cellular mechanisms behind improved function following STT during SCD and test the hypothesis that non-cell autonomous effects on BM HSPCs contribute to their restored function. Via this work, we will establish the pre-clinical rationale for STTs as a tool to improve the function of HSPCs in individuals with SCD, which has major implications for the emerging field of potentially curative therapies for SCD.

Texas Education Agency

STEM education initiative grants for TX to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

Textron Foundation

Supports workforce development, STEM education, and community programs in Textron brand communities.

NCI - National Cancer Institute

Abstract The FASEB SRC TGF-β family in Development and Disease in 2026 (hereafter "TGF-β 2026") will convene investigators who are advancing TGF-β research, from fundamental discovery through clinical application. This gathering unites researchers across the full spectrum of the TGF-β family, which encompasses over 30 ligands including TGF-βs, BMPs, GDFs, activins, and inhibins, who are driving innovations in cancer immunotherapy, regenerative medicine, vascular therapeutics, and age-related interventions. The conference program emphasizes mechanistic insights that inform therapeutic development, featuring sessions on cancer signaling mechanisms, development-disease intersections, vascular physiology and angiogenesis, tissue homeostasis, stem cell biology and regeneration, structure-function, and strategic therapeutic avenues. These presentations will showcase how advances in understanding TGF-β pathway regulation are being translated into clinical solutions for cancer, cardiovascular disease, immune disorders, musculoskeletal conditions, and aging-related pathologies. TGF-β 2026 represents the 14th iteration of this premier conference series, now spanning nearly 25 years of scientific evolution that has paralleled the field's maturation from basic signaling studies to therapeutic targeting. The sustained research momentum, with continued high publication and funding rates across TGF-β research domains, reflects the field's transition toward clinical impact and commercial development. This conference also bridges academic discovery with industry innovation, featuring speakers from leading pharmaceutical companies alongside academic researchers, creating opportunities for translational partnerships and therapeutic advancement discussions. The 2026 meeting will also foster cross- continental partnerships that have become essential for modern therapeutic development. Drawing from 13 previous conferences, TGF-β 2026 provides an intensive forum for sharing evaluating therapeutic targets, discussing regulatory pathways in model systems, and addressing translational challenges. The conference particularly emphasizes developing the next generation of TGF-β researchers equipped for the increasingly interdisciplinary and translational nature of the field, ensuring continued progress toward therapeutic breakthroughs that benefit human health.