Grants

NCA Contracting

Development of Research-based Educational Outreach Materials

Educationresearch

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Development of Selective Antiviral RNA-Degrading Chimeras Mimicking Ribonuclease Activity

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Endogenous ribonucleases (RNases) are an important component of the host immune response to viral infections. Mimicking the RNase function, RNA-degrading chimeras (RDC) are a class of molecules that selectively bind RNA and recruit RNases, typically RNase L, to cleave the viral RNA. However, RNase L- dependent RDCs typically achieve only ~75% RNA knockdown, insufficient for complete viral clearance. To overcome this limitation, we propose to develop a novel class of direct-acting antivirals: RDCs that cleave RNA directly through general acid–general base catalysis, more faithfully mimicking the mechanism of natural ribonucleases. Additionally, we will improve the selectivity of RNA-binding scaffolds by targeting a conserved viral RNA structure and developing a high-throughput synthesis and screening pipeline. Importantly, we will implement a second-generation chemical-guided SHAPE sequencing (cgSHAPE-seq) technology for activity- based RNA profiling. This platform will enable competitive, transcriptome-wide evaluation of ligand binding specificity in live cells. We will demonstrate the effectiveness of this new approach to antiviral design in the context of Zika virus (ZIKV), a mosquito-borne flavivirus associated with severe neurological disorders, including Guillain-Barré syndrome and microcephaly. We hypothesize that our optimized RDCs will significantly reduce ZIKV RNA levels both in vitro and in ZIKV-infected human neural progenitor cells. This project represents the first application of RDCs to directly degrade ZIKV RNA and introduces a generalizable strategy for RNA-targeting antiviral development. By establishing robust methods for RNA binding optimization and transcriptome-wide selectivity profiling, this work has the potential to revolutionize antiviral drug discovery and provide a scalable approach to combat emerging RNA viral threats. 1

Up to $442K

2028-05-31

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Development of Self-Assembling Pyrrole-Imidazole Polyamides for the Treatment of Friedreich’s Ataxia and Prostate Cancer Using Proximity-Induced Bioorthogonal Chemistry

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Developing a new drug typically takes over a decade and costs over $500 millions dollars. Despite this, 90% of drug candidates fail in clinical trials, often due to undesired off-target effects or poor pharmacokinetic (PK) properties. One promising strategy that could overcome these issues and provide a new level of control over therapeutic activity would be the in-situ assembly of a drug at the site of interest. Rather than administering a single compound, two smaller, inactive fragments can be delivered that selectively combine at the target site to furnish the active drug. Lower molecular weight compounds display enhanced PK properties, such as high membrane permeability, due to their smaller size and could avoid off-target effects by only combining at the site of disease. This approach could address PK issues that are inherently associated with the growing demand for large bifunctional molecules that break Lipinski’s rule of five, such as proteolysis-targeting chimeras. This strategy has seldom been explored as identifying a bioorthogonal reaction that will selectively unite the fragments—present only in low concentrations in a cell—remains challenging. The studies described in this proposal seek to develop strategies for the design of self-assembling pyrrole- imidazole polyamides (Py-Im PA), small molecules that can bind DNA and control gene expression, potentially stopping disease at its root. Numerous Py-Im PAs have been developed to treat different diseases yet there are no FDA-approved Py-Im PA pharmaceuticals, in part due to their poor PK properties. By leveraging the natural binding of these compounds to DNA to generate a high local concentration and template a proximity-induced bioorthogonal reaction, one could achieve their selective in situ self-assembly. In Aim 1, a self-assembling linear Py-Im PA that targets the DNA triplet repeats that cause the incurable neurodegenerative disease Friedreich’s ataxia will be designed and evaluated. This PA previously showed promise in cellulo yet suffered from poor membrane permeability due to its high molecular weight. In Aim 2, a proximity-induced azide-alkyne cycloaddition for the in situ synthesis of hairpin polyamides from their linear fragments will be developed. A hairpin Py-Im PA that binds the prostate-specific antigen promoter androgen response element for the treatment of prostate cancer will be prepared. Performing this research in Prof. Bertozzi’s group at Stanford aligns well with their success with developing bioorthogonal chemistry (2022 Nobel prize) and will augment my prior training in organic synthesis to prepare me for a future academic career as a professor. Overall, the proposed research is significant because it could unlock the therapeutic potential of Py-Im PAs for the treatment of Friedreich’s ataxia and prostate cancer by improving their PK properties. This proposal is unique as it represents the first in-situ self-assembly of PAs in cellulo from more bioavailable components. More broadly, this proposal represents a novel approach to addressing PK issues in drug design and could be expanded to solve long-standing challenges encountered by other drug candidates.

Up to $76K

2029-02-15

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Development of Smoldyn

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY / ABSTRACT Modeling and simulation are essential to modern cell biology research, but modeling tools have not kept pace with experimental work. In particular, many of the subcellular structures that are routinely investigated by modern microscopy methods can only be modeled at present with custom software. This is because no general-purpose simulators can simultaneously represent proteins, filaments (e.g. DNA and actin), and membrane dynamics. Such capability is essential for investigating fundamental cellular processes such as transcription, cell division, endocytosis, and cell motility. We will develop the necessary algorithms and implement them in our existing Smoldyn software, a widely used tool that is a leader in the spatial modeling field. One of our algorithm sets will focus on filament dynamics. It will accurately capture bending, twisting, branching, and excluded volume effects for filaments, along with interactions between filaments and both molecules and surfaces. These interactions will support simulation of molecular motors, DNA transcription, and feedback from filament- bound proteins to the filament conformations. Our algorithms will represent filaments at a high level of detail and will simulate efficiently through the use of multiple solvers that are optimized for different parameter options. Another algorithm set will focus on membrane dynamics, such as deformation, endocytosis, and cell division, along with the intracellular interactions that arise in those processes. The resulting simulator will be able to model a wide range of elementary cell biology processes and, by extension, most of the complexity of real cells. Our research team includes members from a lab that combines experimental and theoretical work. They will use our software, as it is developed, to model actin assembly against load from membrane elasticity and actin-driven endocytosis. This portion of the work will help motivate and direct the methods development work because it will use a wide range of our new software features. It will also be important in its own right because it will address open questions about the reciprocal relationships between actin- driven forces, actin architecture, and membrane shape in endocytosis. We will continue to work closely with the broader biochemical modeling community through software support and help with integrating our software into other tools as a back-end physics engine. We will also work with the community in the ongoing development of a standardized language for describing spatial cell biological models. We anticipate that our work will have a high impact in cell biology research because it will enable realistic spatial modeling for systems that cannot be modeled at present with existing tools. Many researchers have directly requested these software features, in person and in letters of support.

Up to $317K

2030-01-31

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Development of solutions to address immediate and longer term needs of Oregon's small- and medium-sized exporters/importers which have been impacted by the departure of trans-ocean container service at the Port of Portland.

Multiple - Trade & Logistics Initiative

Development of solutions to address immediate and longer term needs of Oregon's small- and medium-sized exporters/importers which have been impacted by the departure of trans-ocean container service at the Port of Portland.

Up to $110K

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Development of solutions to address immediate and longer term needs of Oregon's small- and medium-sized exporters/importers which have been impacted by the departure of trans-ocean container service at the Port of Portland.

Multiple - Trade & Logistics Initiative

Up to $80K

Free to search & build · $99 one-time to unlock the application pack · No subscription

Development of Swajchuk Park as a centralized recreation facility

DEEP

Development of Swajchuk Park as a centralized recreation facility

Up to $200K

Free to search & build · $99 one-time to unlock the application pack · No subscription

Development of technologies for elucidating the function of cryptic intergenic regions within genomes

NIGMS - National Institute of General Medical Sciences

ABSTRACT This project aims to revolutionize genome annotation by creating new technologies to detect and annotate genomic features currently hidden within intergenic regions. Intergenic features are underexplored and often overlooked by popular genome annotation software despite their vital importance to genome functioning. For example, existing automatic annotation programs miss small proteins due to minimum size cutoffs and are unable to detect non-coding RNAs that are unrepresented in curated databases. These omissions leave the appearance of empty intergenic space that, in fact, contains genomic features. The problem of incomplete annotations is particularly acute for prokaryotic genomes, which are immensely diverse and heavily reliant on automated annotations. This proposal seeks to overcome current limitations, such as the difficulty of detecting ambiguous or rare features, by leveraging machine learning, comparative genomics, and new methodologies for identifying non-coding RNAs, small proteins, and regulatory elements. The proposed technologies will not only improve the accuracy of genome annotations but also enable the discovery of new genomic features that could have significant implications for biomedical research, including the identification of new drug targets. In Aim 1, we will develop a program for finding protein coding genes in prokaryotic genomes that draws upon novel signatures of true genes to improve accuracy over existing methods. In Aim 2, we will identify undiscovered non-coding RNAs by leveraging machine learning with creative signals that differentiate non- coding RNAs from intergenic space. In Aim 3, we will apply comparative genomics methods to clarify the probable function of enigmatic non-coding RNAs. Collectively, these technologies will shed light on unannotated intergenic space and democratize genome annotation by providing an advanced software for comprehensively annotating a broader range of organisms.

Up to $1.9M

2030-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Development, Refinement, and Validation of Sensitive and Robust AO-OCT Glaucoma Biomarkers

NEI - National Eye Institute

PROJECT SUMMARY/ABSTRACT Glaucoma is a leading cause of irreversible blindness worldwide, resulting from progressive damage to retinal ganglion cells (RGCs). Current diagnostic methods detect disease only after significant structural and functional loss, and existing metrics for disease progression require extended monitoring periods, limiting the feasibility of clinical trials for neuroprotective therapies. There is an urgent need for robust, mechanistically relevant biomarkers to enable earlier detection of glaucoma progression and facilitate the development of novel therapeutics. This project aims to refine and validate advanced imaging biomarkers using Adaptive Optics-Optical Coherence Tomography (AO-OCT), a high-resolution imaging modality that permits direct visualization of RGC soma and vascular mural cells, including pericytes, in both animal models and human subjects. Preliminary data indicate that AO-OCT can detect early morphological changes in RGC soma and pericytes associated with glaucoma progression. However, further validation and improvement of these biomarkers are necessary before larger-scale clinical trials can be conducted. The proposed study consists of two specific aims. In Aim 1, we will utilize transgenic mouse models to confirm the specificity of AO-OCT biomarkers for RGCs and pericytes and to longitudinally assess cellular changes in two established glaucoma models. This work will provide critical validation of AO-OCT imaging against gold- standard histological techniques. In Aim 2, we will conduct a two-year longitudinal study of 50 human subjects with mild glaucoma to assess the relationship between AO-OCT biomarkers and conventional clinical measures of disease progression. Additionally, we will develop AI-based vessel segmentation techniques to enhance the precision of pericyte identification and characterization. This research will yield highly sensitive and specific biomarkers for glaucoma progression, enabling more efficient and cost-effective clinical trials for neuroprotective therapies. Ultimately, these advancements will improve early diagnosis, facilitate the development of novel treatments, and reduce the global burden of blindness due to glaucoma.

Up to $571K

2030-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Developmental Activity and Function of Layer 5 Cortical Circuits Following Early Postnatal Reorganization

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY The precise formation of circuits in the cerebral cortex, involving both excitatory pyramidal neurons (PNs) and inhibitory interneurons (INs), is crucial for proper brain function, with disruptions in this process being implicated in neurodevelopmental disorders such as autism, epilepsy, and schizophrenia. Recent work from the Fishell Lab has revealed that the connectivity of neurons in layer 5 (L5), a critical region for top-down information processing, follows a highly specific targeting pattern that arises during postnatal development. Specifically, in primary visual cortex (V1), L5 is comprised of two distinct excitatory populations—intratelencephalic (IT) and extratelencephalic (ET) neurons—both of which are modulated by inhibitory somatostatin-expressing cortical interneurons (SST cINs). Notably, specific subtypes of SST cINs, such as Chrna2 and Calb2, selectively target ET populations in adulthood. However, it remains unclear whether these targeting patterns are innate or develop over time. Preliminary findings suggest a novel hypothesis: SST cINs may initially target IT neurons and later shift their targeting specificity to ET neurons after eye-opening (P14) in mice, implying a dynamic developmental switch. This transition could be influenced by changes in excitatory drive, considering that retinotopic maps in V1 are shaped by spontaneous waves of activity both prior to and during eye-opening, while feedforward excitation from visual experience appears necessary for the proper maturation of visual responses. The goal of this proposal is to investigate the mechanisms driving this developmental switch and its functional implications. To do this, the study will (1) examine activity patterns of L5 SST cINs, IT, and ET populations across key developmental timepoints (P10, P15, P30) using 2-photon calcium imaging, (2) determine whether the switch in SST cIN targeting influences activity within L5 circuits or the ability of the animal to detect visual stimulus through use of targeted expression of Kir2.1 in SST cINs which prevents the switch in synaptic targeting, and (3) assess whether visual experience is necessary for the proper development of these circuits by rearing mice in darkness and analyzing the effects on L5 activity and circuit formation. By elucidating the activity-dependent processes that regulate the development and refinement of cortical circuits, this project aims to improve our understanding of how disruptions in these processes contribute to neurodevelopmental disorders.

Up to $76K

2029-02-28

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Developmental age specific neuroprotective therapies for perinatal brain injury

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Perinatal brain injury such as hypoxic-ischemic encephalopathy (HIE) is associated with a high risk of mortality and morbidity including intellectual disability, cerebral palsy, epilepsy, hearing or vision impairment. No therapies currently for late preterm(34-36 weeks’ gestation) HIE , which falls in a research gap between term (37-40 weeks’ gestation) HIE treated with therapeutic hypothermia and preterm white matter injury frequently seen in infants born <32 weeks’ gestation. Importantly, even when the etiology of injury is similar, there is limited evidence to suggest that the same therapeutic strategy will be effective for late preterm and term infants born with 2-4 weeks’ difference in gestational age at birth. Our recent preliminary data in late preterm and term equivalent rat models of newborn brain injury suggests there is a loss of neuroprotective effect of an anti-inflammatory, anti-oxidant agent with increasing developmental age at onset of injury. To determine if developmentally specific therapies are needed for neonatal brain injury, our objective is to evaluate curcumin-encapsulated biodegradable nanoparticles with high curcumin loading (40% by weight) and controlled release in late preterm and term brain injury. Curcumin has antioxidant, anti-inflammatory, and anti-apoptotic effects; however, curcumin’s therapeutic applications are restricted due to low aqueous solubility, low bioavailability, instability in light, and rapid first-pass hepatic metabolism. Polymeric nanoparticles can provide high drug encapsulation efficiency and sustained release of a therapeutic, in addition to improving drug solubility, circulation kinetics, and parenchymal distribution and cellular uptake in the brain. We have shown upon systemic administration that curcumin-loaded poly(lactic- co-glycolic acid) poly(ethylene glycol) (PLGA-PEG) nanoparticles localized in injured regions of the brain and reduced acute neuronal and global brain injury after cerebral hypoxia-ischemia (HI) in a late preterm rat. Our overall hypothesis is that curcumin-loaded nanoparticles will lead to long-term reduction in neuroinflammation and oxidative stress, and improved behavioral outcomes after neonatal HI brain injury, with greater efficacy in the late-preterm model than the term model. In Aim 1, we will evaluate nanocurcumin for neuroprotection in late preterm and term neonatal HI brain injury. We will measure oxidative stress and inflammatory markers, and quantify PLGA-PEG and curcumin uptake and localization as a function of blood-brain-barrier impairment. We will then evaluate the neuroprotection afforded by two dosing schemes of cucumin-loaded PLGA-PEG in the late preterm and term neonatal HI model to determine the most effective dosing scheme for reducing global brain injury and total area loss, improving neuropathological outcomes, and mitigating inflammation and oxidative stress. Using the most effective dose from Aim 1, in Aim 2 we will assess long-term neuropathology and behavioral outcomes of curcumin neuroprotection in late preterm-equivalent rats after HI. Successful completion of this study will result in a promising nanotherapeutic platform for late preterm brain injury and inform therapeutic development for different developmental ages at injury onset.

Up to $406K

2028-04-30

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Developmental and cell type specific histone gene expression patterns

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY: Histone proteins are critical for the compaction and organization of newly synthesized genomes. Histone protein concentrations help regulate the timing of rapid cell divisions in the early animal embryo. Misregulation is developmentally lethal: histone overexpression leads to extra or asynchronous cell divisions, while reduced histone expression leads to cell cycle arrest. As embryos develop, cell division dramatically slows. This change in the cell cycle leads to radically differing demands for histone transcripts and variable rates of histone gene expression. Cells must quickly alter their histone expression dynamics to match their cycling needs. Unequal demand for histone transcripts is perpetuated later in development as diverse cell types acquire novel proliferative potentials. Because of the ubiquitous necessity of histone proteins, genomes often carry many copies of each histone that are nearly identical in sequence, which may be clustered or distributed. This creates a unique regulatory problem in differentiating cells because histone genes are indiscernible from each other. A longstanding, major assumption in the field is that histone genes are largely regulated in concert: all histone genes are expressed or silenced to the same degree. I aim to fill this fundamental knowledge gap by tracing histone transcripts to both gene and locus of origin to determine how identical histone genes are expressed throughout development to maintain proper proliferative potential. I will test my hypothesis in two specific aims: In Aim 1, I will test how clustering of histone genes affects expression by engineering a transgenic D. melanogaster that includes sequence variation in histone coding regions. This allows for the tracing of transcripts to their gene of origin. I will perform RNA sequencing to compare mRNA dynamics from individual histone genes through an embryonic time course as the cell cycle lengthens. These experiments will determine how the expression patterns of individual genes within a cluster change with dynamic cell division requirements. In Aim 2, I will test how separating histone genes between loci alters regulation by utilizing the natural genomes of Drosophila virilis and D. simulans/transgenic D. melanogaster hybrids, whose genomes carry two histone loci of different sizes (D. virilis) or similar sizes (hybrids). I will leverage natural histone coding sequence variations in both species to perform single nucleotide variant fluorescent in situ hybridization, visualizing locus-specific transcriptional patterns in differentiating neural cells. These experiments will define regulatory strategies that attenuate histone expression as cells differentiate and the cell cycle slows. Overall, these aims illustrate how identical sets of histone genes are differentially regulated during early animal development, which is crucial to our understanding of developmental cellular differentiation and proliferation. I designed these experiments, in collaboration with my sponsor and co-sponsor, to address critical knowledge gaps in our field, develop expertise in a broad array of techniques, and provide me with the training opportunities to become an independent researcher.

Up to $50K

2029-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Developmental control of inflammatory memory in atopic dermatitis-like skin disease

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Abstract Atopic dermatitis (AD) is a chronic skin condition characterized by T cell-driven Type 2 inflammation. The MC903- induced dermatitis model has enabled dissection of pathways driving acute AD-like disease such as keratinocyte TSLP production and Th2 signaling; however, its ability to model persistent disease states remains unexplored. Using a repeated-challenge protocol with MC903, we found that adult mice undergoing a primary bout of AD-like inflammation develop persistent, tissue-specific inflammatory memories in skin that manifest as exaggerated pathologic responses during secondary MC903 challenge. This aligns with the emerging idea that AD chronicity stems from local memories of inflammation that persist in healed lesions and exacerbate future disease flares. However, AD in childhood follows a distinct course, with a unique immune composition and lower incidence of chronic disease. We thus tested our model in neonatal mice, and despite observing similar primary response kinetics to MC903-treated adults, we strikingly saw no signs of aggravated pathology during secondary MC903 challenge. This suggests that AD-like inflammatory memory fails in early life. Characterizing the cellular and molecular mediators of these divergent skin phenotypes will be the focus of our proposed work. Our data suggests that inflammatory memory in adults is driven by the emergence of Type 1 (T1) immune features in skin such as T1 tissue-resident memory T cells (Trms), mirroring recent findings in human AD. Transcriptional profiling suggests fibroblasts help to organize these networks by supporting T cell positioning and Trm development within inflamed adult skin. Given emerging data to suggest that neonatal T cells and fibroblasts exhibit distinct inflammatory behaviors from their adult counterparts, we hypothesize that inflammatory memory is impaired in neonatal skin due to age-related differences in T cell and fibroblast function. To test this, we will first use lineage tracing to define the fates and phenotypes of adult and neonatal T cells during AD-like inflammation in developing and adult skin (Aim 1). Subsequently, we will interrogate fibroblast-T cell interactions in the atopic skin of adult and neonatal mice using in vivo profiling via scRNA-seq and immunofluorescence staining as well as in vitro functional assays involving fibroblast-T cell co-cultures. Our work is conceptually innovative and clinically relevant, especially given the growing incidence of chronic AD in adults. Completion of the proposed work will clarify the basic mechanisms by which neonatal skin escapes inflammatory memory, potentially aiding in the identification of new therapeutic interventions for chronic AD.

Up to $44K

2028-12-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Developmental Mechanisms of Joint Attention During Parent-Infant Play Among Infants at High Familial Likelihood of Later Autism Diagnosis.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Visual attention is one of the most robust early indicators of autism, a neurodevelopmental condition characterized by persistent difficulties in social communication - including joint attention (JA), which refers to the ability to simultaneously attend to a target of interest with another individual. Recent research has given considerable focus to studying JA experiences among infant siblings of individuals diagnosed with autism (HFL - high familial likelihood for later autism diagnosis), given the documented link between JA experiences and later developmental outcomes (e.g., autism diagnosis) in this clinical population. However, studies of JA among HFL infants are often limited to screen-based eye-tracking tasks (that are devoid of social context) and subjective observational coding during structured play tasks (which are prone to reliability issues or rely on explicit cues to elicit JA). Importantly, the characterization of JA relies on simple shared attention to a target and does not accurately reflect the extent of the cognitive resources deployed by the infant to process the target. Recent electroencephalography (EEG) studies with screen-based eye-tracking tasks have revealed neural indices associated with attentiveness that may serve as critical differentiators between infant engagement and disengagement during JA episodes - however, these studies are limited to infants with low familial likelihood for later autism diagnosis (LFL), despite considerable EEG work linking neural activities within the first year of life to later autism diagnosis. Consequently, there is a lack of understanding about how infants’ brains learn to pay attention within complex, dynamic, and ecologically valid social settings - such as during parent-infant play, where parents are known to actively support JA experiences. To address these issues, the proposed goal of the current study are to implement a new technology that combines head-mounted eye-tracking with EEG recordings to simultaneously record HFL infant attention and neural activity within a social parent-infant play session to explore the following questions: (1) how parental social scaffolding supports JA, (2) how neural indices are related to JA, and (3) how infant neural activity during JA responds to parental social scaffolding. This study aligns with the National Institute of Health’s (NIH) vision and mission of seeking fundamental knowledge about cognitive mechanisms that have the potential to advance early parent-mediated autism interventions offered to families and their children. Ultimately, this project aims to provide essential and innovative research in the area of infant siblings of individuals with autism, while also training a promising new investigator in ethical, methodological, neuroinclusive, and interdisciplinary research practices.

Up to $40K

2028-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Developmental mechanisms underlying the functional diversification of facial motor neurons

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY/ABSTRACT During development, neurons that are generated at a single location can go on to innervate different targets and carry out different functions. A fundamental question in developmental neurobiology is to understand how this functional diversification occurs. The developing brainstem gives rise to facial branchiomotor neurons (FBMNs), which innervate different sets of muscles in the face and collectively control all facial movements. While the developmental programs specifying FBMNs are well understood, differences between FBMNs that enable them to wire to different upstream neurons and muscle targets to control different behaviors remain poorly understood. Agenesis, miswiring, and other developmental anomalies of FBMNs cause Congenital Cranial Dysinnervation Disorders (CCDDs), characterized by clinical presentations including facial paralysis, depending on which neurons are affected. A better understanding of FBMN development will also advance our understanding of the etiologies of CCDDs. The evolutionary conservation of FBMNs enables investigation in the transparent zebrafish embryo. To identify transcriptional heterogeneity among developing FBMNs, single-cell RNA sequencing and in situ hybridization were used, identifying two transcriptionally distinct populations in the facial motor nucleus, the brainstem structure composed of FBMN cell bodies. The positions of the two transcriptional populations correlate with developmental age: earlier-born neurons migrate to ventral positions and express different genes than later- born neurons, which migrate to dorsal positions. While previous studies have identified some topography in the facial motor nucleus, the relationship between topography, birth order, and gene expression remains unclear. These observations raise the possibility that birth order specifies distinct gene expression programs, which specify innervation targets. Aim 1 proposes to use high-resolution live imaging to uncover the organization of the facial motor nucleus and determine whether this organization is a product of developmental timing. Aim 2 proposes to combine rapid reverse genetic screening and multiplexed single-cell transcriptomic phenotyping to identify functional regulators of facial motor nucleus development, with specific insight into the etiology of the CCDD, Hereditary Congenital Facial Paresis.

Up to $47K

2029-03-15

Free to search & build · $99 one-time to unlock the application pack · No subscription

Developmental Potential of IN-TACKs

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT HIV-1 infection remains a global health crisis. While highly active antiretroviral therapy (ART) allows most people to live with HIV, ART is not curative. HIV-1 exists within a reservoir of latently-infected cells as an integrated provirus DNA that is rekindled for virus gene expression and viral recrudescence upon ART cessation. The field of HIV Cure is accordingly constantly developing new ways, on the one hand, to permanently silence HIV-1 gene expression (block and lock), or, on the other hand, to enhance gene expression and then to eliminate HIV+ cells from the body (shock and kill). HIV-1 structural proteins and replication enzymes are expressed from proviral DNA as Gag and Gag-Pol polyprotein precursors, respectively, which are cleaved into constitutive components by the viral protease (PR) enzyme during virus assembly and maturation. Retroviral PRs are quasi site specific enzymes, and retroviruses have accordingly evolved to regulate PR activity to limit the extent of cellular proteolysis, which otherwise could be leveraged to detect the virus as a foreign invader. Indeed, the field has in recent years described effective small molecule kill modulators, called RT-TACKs, because they work by engaging the reverse transcriptase (RT) domain within Gag-Pol to effect premature Gag-Pol dimerization, which in turn prematurely activates the viral PR to cleave cellular inflammasome modulators and elicit pyroptotic cell death. In addition to protease and RT, the integrase domain encompasses part (the C-terminal portion) of Gag- Pol. Integrase has previously been implicated in regulating PR activity during HIV-1 maturation, but the underlying molecular mechanisms have remained unclear. In this study, we have assessed if integrase-targeting compounds might also elicit pyroptotic cell death. The work described in this application will determine the developmental potential of integrase-targeted activator of cell kill (IN-TACK) compounds for elimination of HIV+ cells.

Up to $267K

2028-04-30

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Developmental Programming of Mitochondrial Function and Pediatric MASLD

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Metabolic-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease affecting adults and up to 40% of children with obesity. A growing body of evidence supports the role of early life stressors in the etiology of MASLD. In humans and animal models, exposure to maternal Western diet (mWD) consumption and obesity during gestation and lactation increases offspring risk for steatosis and more severe metabolic- associated steatohepatitis (MASH). MASH involves the recruitment of bone marrow derived monocytes to the liver, which give rise to macrophages (Mφ) that are unable to resolve inflammation or repair damage, accelerating liver fibrosis. Previous studies show mWD skews bone marrow (BM) derived Mφ (BMDMs) toward a proinflammatory phenotype by remodeling fetal hematopoietic stem and progenitor cells (HSPCs). Importantly, HSPC programming persists long-term, as BMDMs from juvenile offspring exposed to mWD in early life are similarly primed for inflammation by an as-yet characterized mechanism that drives inflammation long term and may contribute to ongoing fibrosis in the juvenile liver. Mitochondrial dysfunction, oxidative stress, and inflammation are hallmarks of Mφ trained immunity but crosstalk between these processes due to mWD and their impact on MASLD are not well understood. Our preliminary data shows that mononuclear cells (MNCs) from BM of 3-week-old mice exposed to mWD have decreased oxidative capacity relative to MNCs from BM of control offspring from chow-fed dams. Therefore, we hypothesize that mWD alters mitochondrial function in HSPCs during critical windows of early development to promote BMDM activation and hepatic inflammation, thereby increasing susceptibility to MASH. The overall goal of this project is to understand the mechanisms for how mitochondria are maladaptive to maternal WD during gestation and/or lactation and how specific pathways contribute to the pathogenesis of inflammation through HSPC remodeling of BMDMs. This fellowship has two aims: 1) determine the impact of mWD exposure during pregnancy and lactation on HSPC and BMDM mitochondrial metabolism in mice at weaning and 2) determine the long-term effect of mWD during gestation or lactation on hepatic Mφ populations, Mφ function, and liver fibrosis in adult offspring following WD challenge. Our approach utilizes metabolomics and proteomics, fluorometry, and respirometry to assess mitochondrial physiology and single cell RNA-sequencing to identify unique populations of hepatic Mφ, capacity for liver repair, and fibrosis in livers of adult mice from the same early life mWD exposures. Completion of this work will provide me with training in mouse research, immune cell metabolism, deeper analysis of mitochondrial physiology, bioinformatics, and use of ‘Omics technologies to use in my next steps in career development. Impact: the work from this fellowship will fill a gap in our understanding of maternal diet’s impact on the pathogenesis of pediatric MASLD.

Up to $79K

2029-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Developmental Sciences

U.S. National Science Foundation

Developmental Sciences

2026-07-30

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Developmental Systems Genomics of morphogenetic timing and facial shape variation

NIDCR - National Institute of Dental and Craniofacial Research

PROJECT SUMMARY The objective of this proposal is to elucidate the complex genetic, transcriptional, and histological landscape underpinning palate morphogenesis by leveraging a systems genomics approach in genetically diverse mice. Craniofacial morphogenesis involves the outgrowth and fusion of facial prominences, which must be coordinated with skeletal specification and differentiation to generate a functional craniofacial complex. Underscoring the sensitivity of this intricate choreography, orofacial clefts (OFCs) are the most common facial anomaly in humans, affecting 1/700 births worldwide. Mouse models provide a key platform for human disease allele discovery owing to recent developments in gene editing that enable rapid validation of novel variants. However, multiple published examples demonstrate the profound effect that mouse genetic background can have on the penetrance and expressivity of craniofacial phenotypes. Thus, our limited understanding of the effect of natural strain variation on developmental processes presents a major challenge to validation of disease variants and our ability to model human congenital malformations. While individual genes are critically required for normal development, it is the collective function of genes and their interactions, modularly organized into gene regulatory networks (GRNs), that control the transcriptional dynamics and timing of morphogenesis and differentiation. Variation in these dynamics likely accounts for normal variation in facial shape but can also underpin craniofacial birth defects. However, feasibility limits studies of genetic variation in developing embryos to only a few genes at a time and experimental models that accurately relate genomic sequence variation to variation in transcriptional dynamics are critically lacking. These challenges complicate a systematic address of genome-scale mechanisms that drive morphogenesis and the potential for pathological outcomes. The complementary Collaborative Cross (CC) recombinant inbred strains and Diversity Outbred (DO) heterogeneous stock combine the genetic and phenotypic diversity of 8 common inbred founder strains of mice in a design optimized for systems-level genetic dissection of complex traits. It has been demonstrated that QTLs for facial shape in adult DO mice are enriched for genes with established function in craniofacial and skeletal development. However, these studies do not address mechanisms of where, when, or how QTL candidate genes influence facial shape. The proposed aims will apply a developmental systems genomics approach to map the influence of genetic variation within a model of palate morphogenesis. Aim 1 will define the temporal dynamics of morphogenetic networks within the segmentally organized upper jaw and identify QTL/eQTL underlying strain differences in developmental timing and palate morphogenesis. Aim 2 will employ single-cell and spatial genomics to genetically dissect the molecular signatures of QTL/eQTL with cellular and histological resolution. Aim 3 will leverage quantitative phenotyping to relate differences in morphogenetic dynamics and resulting morphology to variation in underlying genotype and thereby derive mechanistic insight into the integration of genomic regulatory systems.

Up to $796K

2031-02-28

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Developmental windows of vitamin D supplementation for optimal metabolic health

NCCIH - National Center for Complementary and Integrative Health

ABSTRACT: Obesity is prevalent among adults (>40%) and children (~20%) in the U.S. and is expected to increase dramatically in the next 25 years. Addressing the obesity epidemic is vital for public health because of its wide range of comorbidities including deadly conditions such as stroke, hypertension, diabetes, heart disease, liver disease, sleep apnea, pregnancy complications, and cancer. Most clinical interventions for obesity target individuals who are already obese. However, a growing body of research demonstrates that obesity can be caused by adverse events during development that drive irreversible effects on metabolic programming. This work highlights a critical need for preventative measures to address the obesity epidemic. Vitamin D is an essential nutrient that has recently been implicated in obesity. This has the potential to impact a large population since up to 80% of pregnant women are deficient in vitamin D (VDD) and emerging studies implicate this may disrupt developmental programming of metabolism and increase offspring susceptibility to obesity later in life. This proposal will leverage our novel mouse model of VDD-induced adiposity (a naturally genetically divergent Collaborative Cross (CC) mouse lineage) to model the human condition so we can better understand the developmental mechanisms driving obesity and target them for effective interventions. The mouse serves as a vital model for studying this important question not only because of its conserved vitamin D biology but also because mouse research allows us to avoid ethical limitations that inhibit studying VDD in human pregnancy and provides control over environmental and genetic confounders present in human populations. The proposed study aims to: (1) Determine the importance of vitamin D sufficiency during pre-, peri-, or post-conceptional windows of development in driving the accumulation of adiposity and risk of obesity-related comorbidities later in life; and (2) Define the developmental timing of VDD-induced transcriptional dysregulation and investigate its role in disruption of metabolic programming. Addressing these gaps in our understanding of the role of VDD in developmental mechanisms of obesity will help determine the relative importance of VitD monitoring and timely interventions for VDD during pregnancy to protect offspring metabolic health so that effective guidance can be developed.

Up to $428K

2028-03-31

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Device Integration into Assisted Living Project

Full Life Care

Conduct workshops to teach low-income Seattle Housing Authority residents about smart speakers and other Internet of Things devices that can enhance daily living for people with disabilites.

Up to $29K