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NINDS - National Institute of Neurological Disorders and Stroke

PROJECT ABSTRACT Absence seizures, characterized by rhythmic 3–4 Hz spike-and-wave discharges (SWDs) on electroencephalography, represent a significant neurological burden affecting thousands of children worldwide. These brief (5-10 second) periods of impaired responsiveness and loss of consciousness are associated with lasting cognitive, sensory, and learning deficits. Despite this clinical impact, the cellular and network mechanisms underlying impaired consciousness and arousal during absence seizures remain poorly understood, limiting options for therapeutic development in pediatric epilepsy. Prior research in rat models of absence seizures has attempted to address this gap and has partially recapitulated the behavioral impairments seen in patients by training rats on behavioral tasks as proxy indicators of consciousness. However, these studies were performed in freely moving rats, limiting the use of advanced cellular and optical methods that require head fixation. Given the broad availability of genetic and molecular tools in mouse models and the feasibility of studying mice in awake, head-fixed conditions, establishing a behaving head-fixed model of absence seizures would be extremely valuable. To this end, this project will use the heterozygous SCN8A mouse model, a well-characterized genetic model of absence seizures, in combination with an awake, behaving head-fixed task paradigm, to elucidate mechanisms of disrupted arousal and auditory processing during SWDs. Aim 1 will optimize a lick-on-cue behavioral paradigm and evaluate cortical acetylcholine dynamics during task performance using fiber photometry to characterize arousal state changes at the neurotransmitter level. Aim 2 will utilize in vivo single unit recordings to identify cortical neurons associated with SWD-disrupted behaviors and characterize distinct firing patterns underlying consciousness impairment. Experiments from Aim 1 will provide the first characterization of chemical mediators of impaired arousal in absence epilepsy, particularly within the auditory primary and association cortex processing network. By correlating single-neuron activity with behavioral impairment severity and establishing morphological identity through juxtacellular labeling, Aim 2 will reveal which specific cortical cell types and firing dynamics underlie consciousness disruption during absence seizures. These findings will advance our fundamental understanding of the neural mechanisms underlying consciousness and arousal, with direct implications for developing targeted interventions for childhood absence epilepsy. The mechanistic insights gained may also inform therapeutic approaches for other neurological conditions affecting consciousness and cognitive function in pediatric populations. This project is well-positioned for success through the integration of strong mentorship, technical expertise from key collaborators, comprehensive training opportunities, and state-of-the-art research facilities.

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY Micro-nano-plastics (MNPs) are small plastic particles resulting from the environmental breakdown of plastic waste over time. These particles have accumulated in ecosystems and entered the food web through contaminated water and food, trophic transfer, and exposure during food processing and packaging. Recent studies have detected MNPs in nearly every human organ and tissue, underscoring their widespread presence. While it is known that MNPs can cross biological barriers like the intestine, the health effects of MNP exposure are still poorly understood, and the mechanisms that allow MNPs to bypass these barriers remain unclear. Additionally, most toxicological studies have relied on simplified MNP models, such as polystyrene beads, which do not accurately reflect the complex physicochemical properties of real-world MNPs. This project aims to bridge these knowledge gaps by exploring the intestinal uptake mechanisms, biodistribution, and impacts on intestinal health of environmentally relevant MNPs. The focus will be on the effects of MNP polymer type, size, surface chemistry (including weathering), and prolonged exposure on MNP toxicity and inflammatory responses. Our central hypotheses are: (I) MNP properties such as size, polymer type, and environmental weathering influence their uptake, translocation, toxicity, and inflammatory effects; (II) MNPs are taken up through both passive diffusion and energy-dependent endocytosis pathways; (III) prolonged exposure enhances MNP uptake by altering gene expression related to cell junctions, endocytosis, and inflammation; and (IV) intestinal inflammation, such as in inflammatory bowel disease (IBD), increases MNP translocation by enhancing intestinal permeability, which further promotes biodistribution. To achieve these objectives, the study is organized into two specific aims: Aim 1: Synthesize and characterize environmentally relevant “tracer” MNPs (Au Core-Plastic Shell) for use in toxicological studies. These physicochemically characterized MNPs will be subjected to weathering/aging processes to simulate environmental conditions, and will enable MNP quantification using ICP-MS. The characterization will focus on the physicochemical properties of MNPs, including size, polymer type, and surface chemistry. Aim 2: Investigate MNP translocation mechanisms and toxicity using advanced in vitro models. This will include a triculture model of the small intestinal epithelium and human Intestine-on-Chip (IOC) models derived from both healthy and IBD donor organoids. Simulated digestion will replicate real-world exposure conditions, and the effects of MNPs on intestinal toxicity, gene expression, and inflammatory response will be examined. In addition to providing state of the art, transdisciplinary training to a doctoral student, the findings from this research will provide critical data for assessing the risks of MNP ingestion, inform regulatory actions, and open new research avenues in toxicology and epidemiology for this emerging environmental pollutant.

NIAID - National Institute of Allergy and Infectious Diseases

The only curative therapy for end-stage heart disease is heart transplantation. Millions of patients (worldwide) could benefit from such therapy but are not eligible for transplantation due to limited donor organ availability, thus, there is an urgent need to develop alternative organ sources. Genetically modified pigs as an organ source for xenotransplantation has met with limited success. An alternative is to engineer a porcine model that is deficient for key developmental regulatory factors, so that the target organ (i.e. heart) is disabled. We hypothesize that these mutant porcine embryonic hosts provide a developmental “niche”, for the healthy donor stem cells to populate and generate a donor-derived organ. Using this strategy, our lab was the first to engineer intraspecies (pig-pig) vasculature in an ETV2 null pig (Nature Biotechnology and Nature Cell Biology) and intraspecies (pig-pig) muscle in a MYOD/MYF5/MYF6 null pig embryo (Nature Biomedical Engineering). These studies were innovative steps forward for the field as they demonstrated for the first time that allogeneic (pig-pig) organs could be engineered in the absence of immunosuppression. We further engineered human vasculature and separately human skeletal muscle in gene edited pigs (thereby rescuing the respective null phenotypes) but these interspecies chimeras were less efficient and novel methods are required to interrogate the barriers that prevent efficient chimerism. We have recently developed a novel aggregation-based culture system that extends porcine embryo development through gastrulation, providing the first ever opportunity to study lineage allocation and interspecies cell interactions without reliance on surrogates. In these studies, we will use our high throughput system to interrogate interspecies cell competition, the advantage of a cardiac specific niche, as well as the production of a macaque heart within a lineage disabled porcine embryo. To examine our hypotheses, we will address the following specific aims: Specific Aim #1: Establish and optimize an in vitro long-term culture platform that supports the development of both wild-type and NKX2-5 null porcine embryos up to early organogenesis; Specific Aim #2: Generate and characterize nonhuman primate (macaque)–pig chimeric embryos using NKX2-5 null porcine hosts; and Specific Aim #3: Generate and characterize a macaque heart in the NKX2-5 null porcine host in vivo. In these studies, we will use state-of-the-art gene technologies and macaque GFP-labeled stem cell populations to engineer a nonhuman primate heart in a gene edited pig. This nonhuman primate large animal model will be an important resource for regenerative medicine and will serve as a platform for generating personalized humanized porcine models. This strategy has the capacity to have a profound impact on the development of emerging therapies for endstage heart failure, transplantation, and the democratization of organ availability for our patients.

NIGMS - National Institute of General Medical Sciences

Abstract Gene editing technologies based on CRISPR-Cas9 are transforming the landscape of molecular medicine by enabling targeted manipulation of nucleic acids. However, critical challenges remain in understanding the fundamental mechanisms that govern their activity, fidelity, and dynamics. The PI’s laboratory has been at the forefront of computational gene editing research, initiating the first molecular simulation of CRISPR-Cas9. Through the integration of advanced computational methods – including free energy simulations, quantum mechanical methods, cryo-EM data processing, and graph theory-based models – the lab has uncovered critical insights into conformational dynamics, catalytic mechanisms, and target specificity. These efforts have also led to the design of novel variants with improved specificity in RNA-targeting CRISPR-Cas systems. Over the next five years, the PI research program will advance the field by integrating physics-based molecular simulations with emerging methods based on Artificial Intelligence (AI). This includes deep learning-based enhanced sampling, Graph Neural Networks (GNNs) to build predictive models based on graph-structured data, and novel causality inference approaches for simulation analysis. Through these methodologies, the lab aims to provide new mechanistic characterization of the conformational rearrangements of CRISPR-Cas9, determine the structure-function relationships in prime editors, and decode how engineered variants achieve enhanced specificity. These innovations will support the broader goal of enhancing the precision and efficiency of gene editing technologies for therapeutic use. The lab’s vision is to fully integrate molecular simulations with deep learning approaches to address emerging questions in the biophysics of gene editing systems, providing novel insights that could lead to a paradigm shift in understanding their function and optimizing their functionality. By leveraging state-of-the-art computational methods integrated with AI – methods never applied before to CRISPR- Cas systems – we will pioneer new approaches to advancing genome editing technologies. This program reflects a long-term vision to establish a computational framework that not only explains existing CRISPR behaviors but also guides the design of future gene editors, in close collaboration with leading experimentalists.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY This proposal seeks to understand the mechanistic basis for diseases caused by loss-of-function missense mutations in the gene encoding Phosphoribosyl Pyrophosphate Synthetase 1 (PRPS1). The PRPS enzyme is conserved from bacteria to humans and it catalyzes an essential chokepoint reaction in cellular metabolism that routes sugars into nucleotide production pathways. Previous work in our lab has revealed that the PRPS enzyme operates as a heteromeric biochemical complex comprised of four PRPS paralogs that arose through a series of gene duplications in the Opisthokonta lineage. Our work also demonstrated the vital nature of this PRPS enzyme assembly, as cells exclusively expressing PRPS1 had diminished fitness metabolically characterized by decreased nucleotide production and defective mitochondrial respiration. We hypothesize that alterations in preferential interactions or changes in conformational dynamics between PRPS1 and other members of the PRPS complex produce the panoply of pathophysiological disease manifestations caused by PRPS1 loss-of- function variants. Further, we hypothesize that regardless of the structural basis for PRPS enzyme deficiency, a convergence on a core set of metabolic dysfunctions will be the outcome, which includes diminished nucleotide production, deregulated redox homeostasis, and mitochondrial respiratory defects. We will test these hypotheses in two of the three aims, which will employ a suite of isogenic fibroblast cell lines harboring CRISPR-mediated knockouts of PRPS paralogs, alone or in combination, in all viable configurations. Reconstitution of the PRPS1 KO clones with wild-type or each of the >30 loss-of-function variants will enable comprehensive structural and metabolic characterization of disease-causing variant effects, thereby generating new knowledge regarding fundamental features of enzyme complex organization, activity, and metabolic pathway control. To move beyond simply understanding the mechanisms that contribute to PRPS deficiency disorders, we also aim to develop and perform proof-of-concept testing on enzyme replacement therapeutic strategies that may ultimately be used to treat human patients with these incurable genetic diseases. Collectively, this proposal will generate new insights into the inner workings of the complicated and poorly understood PRPS enzyme complex and its control of cellular metabolic pathways and fluxes. Successful completion of our proposed studies will aid in the understanding, diagnosis, and treatment of PRPS deficiency disorders like Sensorineural Deafness (DFNX1), Charcot-Marie-Tooth disease (CMTX5), and Arts syndrome that are caused by missense loss-of-function mutations in PRPS1.

NHLBI - National Heart Lung and Blood Institute

SUMMARY Rapid eye movement sleep (REMS) is regulated by dynamic interactions between REMS-promoting (REM-on) and REMS-suppressing (REM-off) neurons. Once REMS is entered, the activity in distinct brainstem nuclei gives rise to its distinct phasic features such as rapid eye movements and pontine (P-) waves, defining hallmarks of phasic REMS. Research within the last decade has identified multiple cell populations that control REMS and mapped their connectivity. However, the population-level dynamics underlying REMS initiation and its phasic features remain poorly understood. In the initial grant phase, we showed that inhibitory neurons in the dorsomedial medulla (dmM) strongly promote REMS via their projections to the dorsal and median raphe. In addition, we identified an excitatory subpopulation expressing corticotropin-releasing hormone (CRH) that reliably induces P-waves. These neurons project to the dorsolateral pons, a critical site for P-wave generation in rodents. In preliminary experiments, we performed high- density electrophysiological recordings in dorsal (DR) and median raphe (MR) and in the dorsolateral pons. Performing dynamical systems analysis, we uncovered two key features: First, the population activity in DR/MR exhibits consistent trajectories passing from an NREM attractor to a REM attractor through a specific entry point, and second, the dorsolateral pons shows bistable dynamics that switch between tonic and phasic REMS states. The central objective of this proposal is to understand how distinct populations in the dmM shape downstream midbrain and pontine population dynamics to facilitate transitions to REMS and regulate phasic REMS. This will be accomplished in two aims. First, we will perform high-density recordings combined with opto- and chemogenetic manipulation and viral tracing to reveal how inhibitory dmM inputs and subpopulations within DR and MR shape the population dynamics to initiate REMS. Second, we will investigate how projections from the dmM to the dorsolateral pons regulate P-waves and phasic REM by combining electrophysiological recordings in pons and medulla with optogenetic perturbation. By integrating state-of-the-art systems neuroscience techniques with dynamical systems analysis, our study will uncover how distinct medullary populations regulate the population dynamics in midbrain and pontine areas to regulate REMS induction and its substage architecture. Since disturbances in REMS, particularly in its timing and phasic features, are key symptoms of mood disorders such as major depressive disorder (MDD), our findings will provide critical mechanistic insights and may identify novel therapeutic targets for restoring healthy sleep in depression.

Freeway Park Association

Freeway Park Association seeks funding to support three complementary projects happening in Freeway Park Dec 24-June 25. We will illuminate pathways with heritage tree lighting; illuminate art and create connections with a community festival; and illuminate history with shared stories and educational signage. The projects include 1. Foundational winter lighting for public delight and much needed safety, and to create a backdrop for our March art activation; 2. An illuminated art event in March entitled `Meeting at the Balance` supporting 6-9 artists/artist teams' art installations, performances, and art making workshops; 3. Creating public education materials about the social and political history of the park and the details of the Park's renovation which is slated for May 25. Meeting at the Balance will energize and illuminate the park, empower and fund local artists and also educate the community about the future and past of Freeway Park at this moment of expansion and change.

206 Zulu

During President's Day weekend of 2019, 206 Zulu will host the Meeting of the Minds Community Arts Forum at historic Washington Hall,153 14th Avenue. This weekend of intensive programming will bring together local leaders, artists, youth, families and nationally recognized pioneers in urban arts activism. The free community showcase will include guest speakers, panels, presentations, art displays and performances from both emerging and established musicians, artists and dancers.

Andrew W. Mellon Foundation

Grants for museums, performing arts organizations, and cultural institutions advancing humanities and artistic practice.

NHLBI - National Heart Lung and Blood Institute

This K24 grant renewal will continue to provide the PI, Dr. Lin Yee Chen, an NIH-funded patient-oriented research (POR) investigator, with the protected time and support needed to (1) accelerate his current trajectory in mentoring physicians and scientists who are conducting POR in cardiovascular disease (CVD), (2) acquire additional training in artificial intelligence (AI)/machine learning (ML) and omics science, (3) promote his current research that aims to use supervised ML and multimodal data integration to improve prediction of CVD and neurocognitive outcomes in people with atrial myopathy. Trainees in his AF/Atrial Myopathy Clinical Research Group will be recruited from the NIH-funded T32 training programs in the University of Minnesota's Division of Cardiology, Division of Epidemiology, and Division of Biostatistics; Department of Medicine Physician Scientist Training Program; K12 and T32 Programs of the CTSI; and graduate programs (MPH and PhD) in the School of Public Health. For his career development, Dr. Chen will hone his mentoring skills and learn new skills in cutting-edge areas (ML and omics science) through focused study, selected coursework, seminars, and guidance from senior collaborators with domain expertise. Finally, this grant will support a research project that is based on the Atherosclerosis Risk in Communities (ARIC) Study and Multi-Ethnic Study of Atherosclerosis (MESA), which extends Dr. Chen’s ongoing work to characterize the clinical importance of atrial myopathy. The specific aims are to develop and validate a multimodal prediction model for incident ischemic stroke (Aim 1), incident heart failure (Aim 2), and incident dementia (Aim 3) in participants with atrial myopathy by integrating a clinical risk score, polygenic risk score, ECG-based, echocardiogram- based, and proteome-based risk models. Models will be validated in the Cardiovascular Health Study (CHS). Our central hypothesis is that integrating multimodal data will improve prediction of clinical outcomes in participants with atrial myopathy compared to unimodal approaches. This project has significant impact: (1) This K24 renewal, which is focused on multimodal data integration and supervised ML, is a logical extension of the PI’s current K24 grant (K24HL155813) that is focused on unsupervised ML to classify atrial myopathy, (2) This K24 renewal will build upon the PI's exceptional mentorship track record. By assembling a team of senior collaborators that comprise experts in AI/ML, molecular epidemiology, and mentoring, the PI provides an outstanding platform for his mentees to acquire cutting-edge skills in POR, (3) By developing and validating comprehensive multimodal prediction models for CVD and dementia, this project will advance the NIH’s Precision Medicine initiative and NHLBI AI Initiative, (4) By integrating state-of-the-art data analytics and rigorous epidemiological methods with the rich resources of deeply phenotyped NHLBI cohort studies, this project will fill critical knowledge gaps in prevention and treatment, thus achieving a sustained and powerful impact on public health, clinical practice, and education of the next generation of researchers in POR.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract: The metabolic analyzer system (MAS) with electrocardiogram (ECG) and plethysmography uses state-of-the-art technology to assess resting cardiac parameters (i.e., aortic calcification), cardiovascular (CV) and cardiopulmonary (CP) response to exercise, energy expenditure, and anaerobic power output (Wingate testing), which are common assessments in clinical and biomedical research in the field of exercise science. This system is of utmost importance in achieving the institution's mission as a student-centered, community engaged institution offering quality higher education focused on career readiness, personal, professional development, and service contributions. The system is necessary to achieve the values of our department-to be student-centric, transformational and collaborative while strengthening our exercise science, biomedical, and pre-allied health courses by providing students with invaluable hands-on training using advanced technology. The system is critical for student and faculty recruitment and retention providing unique opportunities for clinical applications and research. The practical and applied training using advanced instrumentation better prepares students for careers in clinical exercise science and related biomedical fields by removing barriers to their academic preparation. Students will gain skills in CV assessment, exercise stress testing, and metabolic analyses offering them a competitive edge in the job market by accumulating hours of hands-on, clinical grade experience, setting them apart from other students in other programs. Additionally, the MAS will strengthen the opportunities for research collaborations across our university and with community partners by providing increased opportunities for transformative research in allied health, exercise science, and health assessments. This MAS is needed for interdisciplinary collaborations among students, faculty, staff, and professionals from various fields {e.g., allied health and behavioral sciences), allowing for partnerships with external institutions, including hospitals, clinics, and neighboring universities by providing assessments and research collaborations. Also, this system is critical for our continued commitment to biomedical research focused on allied health by providing assessments to the underserved members of our rural community, veterans, first responders, and student athletes by testing efficiency of caloric output, power production, and CV/CP functioning. This MAS will directly prepare these students for careers in exercise physiology and/or clinical exercise physiology as these concepts are taught in many of the upper-level and graduate courses in their degrees. This hands-on training with clinical-grade instrumentation will prepare our students for better internship experiences in hospitals, cardiac rehabilitation centers, and clinical exercise physiology facilities, making them more competitive candidates and enhancing their ability to contribute meaningfully to patient care during their clinical rotations. Additionally, this instrumentation is needed for students preparing for their ACSM Certified Clinical Exercise Physiologistse exams and for pursuing accreditation of our degrees in this field.

NHLBI - National Heart Lung and Blood Institute

Heart failure with preserved ejection fraction (HFpEF) is a systemic disorder affecting 3-4 million patients in the USA, predominantly older women. HFpEF leads to a significant loss of muscle strength and power (contractile dysfunction), contributing to disability, increased risk of falls, and death. Our proposal focuses on contractile dysfunction, which has been linked to mitochondrial impairments. However, the exact connection between metabolic abnormalities and loss of strength and power remains unclear. We have developed rat model that, in male and female animals, mirrors the cardiometabolic features and peripheral myopathy of HFpEF in patients. This model revealed a potential link between mitochondrial and contractile dysfunction in HFpEF involving accumulation of a TCA cycle metabolite that causes post-translational modification of sarcomere and EC-coupling proteins. Aging and HFpEF decrease TCA cycle and mitochondrial ETC enzymes that promote the accumulation of TCA cycle metabolites. Our data show that patients and rats with with HFpEF have increased post-translational modification by TCA cycle metabolites. Limb muscles from rats with HFpEF also have decreased abundance of the key enzyme responsible for reversing the post-translational modification. Ex vivo acute exposure of healthy muscles and single fibers to TCA cycle metabolite that accumulates in HFpEF increased post-translational modification of sarcomere and Ca2+ handling proteins and replicated the loss of force and power seen in HFpEF. Our central hypothesis is that PTM modifications of Ca2+ handling and sarcomeric proteins induced by TCA cycle metabolite impair Ca2+ release and contractile machinery structure- function, causing loss of force and peak power in postmenopausal HFpEF. The first aim is to investigate the mechanisms and establish the role of contractile dysfunction caused by TCA cycle metabolite in healthy muscle and rats with HFpEF. The second aim is to define the biophysical and biochemical mechanisms of contractile dysfunction in older women with HFpEF. We will focus on patients with advanced HFpEF and diagnosis including invasive hemodynamics (gold standard). Our studies in both aims will use comprehensive and complementary state-of-the-art techniques including intact muscle and single fiber contractile properties and [Ca2+], x-ray diffraction, ATPase activity in single fibers, high-frequency (4 kHz) oscillations to examine sarcomere level mechanics, electron microscopy, proteomics, mitochondrial phenotyping, and histology. The studies proposes are critical to provide insights on structural and biochemical modifications that impair function, establish optimal targets to combat loss of force or power using small-molecule modulators of Ca2+ release or sarcomeric proteins, and reveal novel mechanisms of postmenopausal HFpEF myopathy.

FIC - John E. Fogarty International Center for Advanced Study in the Health Sciences

Weight gain following initiation of integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is a major emerging public health threat, significantly increasing risks for dyslipidemia, systemic inflammation, hypertension, diabetes, and cardiovascular disease among people with HIV (PWH) in both the United States (U.S.) and globally. Addressing this challenge is a priority for U.S. health, as identifying why some individuals experience "excessive" weight gain (well beyond “return to health” weight gain) will enable earlier, targeted interventions in at-risk U.S. populations. This research environment cannot be replicated in the U.S. due to extreme clinical heterogeneity: the U.S. Food and Drug Administration (FDA) has approved 26+ individual ARV medications across 7 mechanistic classes, leading to diverse prescribing patterns in which only ~52% of patients follow recommended initial regimens. Furthermore, the median U.S. ART treatment duration is 9.8 years, creating a complex history of prior drug exposures that act as significant confounders in metabolic studies. In contrast, Nigeria uniquely offers a high volume of new HIV diagnoses and a near-uniform use of TLD (tenofovir/lamivudine/dolutegravir). This uniformity provides a unique "natural laboratory" that yields faster, more direct answers about metabolomic and lipidomic signatures by eliminating the noise introduced by varied drug histories. Consequently, these findings can be scaled and adapted globally, directly benefiting the U.S. by informing next-generation diagnostic tools, treatment strategies, and prevention modalities. We hypothesize that substantial early weight gain on TLD is driven by distinct alterations in metabolic and lipid pathways. To test this, we will: 1) Determine the effect of substantial early weight gain on TLD on insulin resistance, blood pressure, dyslipidemia, and inflammation. We will enroll previously ART-naïve patients who initiated TLD regimens (n=200 total) in northern Nigeria and gained <3% body weight (n=100) versus >10% body weight (n=100) over their first 12–24 months of therapy. 2) Determine the metabolic and lipid pathways associated with weight gain during the first 12 months of TLD exposure using metabolomic and lipidomic profiling. We will enroll 60 ART-naïve patients initiating TLD and collect longitudinal sociodemographic, behavioral, clinical, metabolomic, and lipidomic data, along with abdominal CT imaging, to characterize visceral adiposity, hepatic density, and alterations in carbohydrate and lipid metabolism among participants with differing weight trajectories.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT Although lipid-lowering therapies have markedly decreased the incidence of atherosclerotic cardiovascular disease (ASCVD), it remains a major determinant of morbidity and mortality worldwide. Recent experimental and clinical evidence underscores the importance of inflammation in driving residual ASCVD risk; but the therapeutic potential of immunomodulation for ASCVD remains limited. In the last several years, intracellular metabolic reprogramming in immune cells has emerged as a key regulator of inflammation in ASCVD. Thus, further investigation into the immunometabolic regulatory networks that govern atheroprogression is predicted to reveal novel therapeutic approaches for ASCVD. Our lab has recently identified methylmalonic acid (MMA), a byproduct of propionyl-CoA catabolism, as vital to macrophage inflammatory processes that exacerbate atherogenesis. Loss-of-function mutations in key propionyl-CoA catabolism pathway enzymes, such as MMAB (cobalamin adenosyltransferase), lead to MMA accumulation. Circulating MMA levels predict cardiovascular mortality and increase with aging. Nevertheless, the causal role of MMA in ASCVD pathogenesis remains unknown. Recent reports demonstrate that MMAB is markedly downregulated in the aortas of patients with coronary artery disease compared to healthy controls, and in murine models of atherosclerosis, we have found that aortic and macrophage Mmab is significantly reduced. Moreover, our preliminary data show that genetic Mmab deficiency and exogenous MMA treatment exacerbate macrophage inflammasome activation, a key contributor to atheroprogression. The specific role that the MMAB-MMA metabolic axis plays in modulating macrophage inflammatory responses in the context of ASCVD remains to be determined. Our central hypothesis is that dysregulation of macrophage propionyl-CoA catabolism promotes atheroprogression through a novel immunometabolic MMA-mediated signaling axis. Using our newly generated myeloid-specific Mmab knockout mice, combined with state-of-the-art transcriptomics, metabolomics, flow cytometry, stable isotope tracer methodology, functional assays and STARNET datasets, we will (1) Elucidate the molecular mechanisms whereby MMA modulates inflammatory signaling in macrophages and (2) Determine the impact of the MMAB- MMA signaling axis on vascular inflammation and atherosclerosis. Completion of these aims will reveal how immunometabolic regulatory networks govern local and systemic inflammation during atheroprogression. Such networks can subsequently be leveraged to design targeted immune-based therapies for ASCVD.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The kinase Akt is a central mediator of insulin signaling. Its activation by insulin occurs when Akt is phosphorylated at two canonical sites, T308 and S473. Other covalent posttranslational modifications also contribute to Akt regulation, such as phosphorylation at alternative residues, acetylation, and ubiquitination. In this grant, we investigate a distinct mechanism of Akt activation: controlled access to a manganese (Mn2+) ion. Mn is an essential trace element that is acquired through the diet and excreted primarily via efflux from hepatocytes into bile. The efflux of Mn is mediated by the canalicular transporter Slc30a10. We have found in mice, cells, and in vitro that increased Mn availability directly promotes Akt activity in hepatocytes, in a manner that does not require upstream insulin signaling. The Mn-induced activation of Akt is sufficient to suppress glucose production, which provides a biochemical explanation for longstanding observations that Mn has glucose-lowering effects in humans and mice. Moreover, we have found that Mn availability is regulated nutritionally, via carbohydrate signaling. In this grant, we will use classic and state-of-the-art biochemical tools to investigate the cellular and biophysical features of the interaction between Akt and Mn. We will furthermore use genetic and dietary interventions in mice to investigate how control over Mn availability contributes to normal physiology and states of overnutrition. Success of this work will reveal a novel mechanism of regulating Akt activity and hepatic glucose production and generate new avenues for research in metabolism and cell signaling.

NIA - National Institute on Aging

SUMMARY Metals are neurotoxic at high doses yet can contribute to motor and cognitive deficits even at environmentally relevant doses. Metals contribute to amyloid β misfolding and tau hyperphosphorylation, which are pathological hallmarks of Alzheimer’s disease (AD) and AD-related dementia (ADRD) risk as well as cognitive decline. Metals also interact with the APOE4 allele to influence AD risk, advance neurodegeneration, and have vascular effects that may further contribute to dementia risk. Metals may thus represent multiple hits for risk of cognitive impairment and dementia. Yet, few cohort studies have comprehensively evaluated the association of metal exposures with mild cognitive impairment (MCI) and AD/ADRD. To fill this knowledge gap, we propose to leverage the NIH-funded Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts of diverse US adults to test the hypothesis that widespread exposure to metals—determined by established and novel biomarkers—is associated with MCI and AD/ADRD risk and with key pathophysiological processes that explain this risk. ARIC and MESA have rich biorepositories, as well as examination, laboratory, omics and clinical data. In these unique and diverse cohorts, we propose to add a metallome profile to quantify metal exposure and internal dose for each participant by measuring metals in urine, blood, and serum at repeated visits in all participants, as well as in brain-derived extracellular vesicles in a subset of participants. Priority metals include lead, cadmium, copper, mercury, manganese and zinc, although other metals will also be measured. We will connect these metallome profiles with rich brain health and multi-omics data (whole genome sequencing, epigenomic/methylomic, transcriptomic, proteomics, targeted and untargeted metabolomics). We will use powerful, state-of-the-art analyses to determine the prospective associations of long-term metal exposures with risk of cognitive decline, MCI and AD/ADRD risk (Aim 1), and with the trajectory of plasma AD and brain imaging biomarkers (Aim 2) in diverse US adults overall and by sex, race/ethnicity, and APOE4 genotype. We will then develop a predictive multi-omics fingerprint that quantifies risk of MCI, AD/ADRD, and cognitive decline due to metal exposures (Aim 3). Because metal exposures are preventable and treatable, adding high-quality measures of the metallome profile to diverse cohorts with longitudinal brain health and extensive omics data will enable this project to contribute key knowledge of the molecular/biological pathways involved in development of cognitive decline as well as identify new targets for the prevention and treatment of AD/ADRD. This work will generate critical knowledge and serve as a robust model for generating highly valuable data that can be leveraged to prevent/mitigate harmful metal exposures and protect cognitive health.

Metcalf Foundation

The Metcalf Foundation supports performing arts innovation, environmental programs, and inclusive local economies in Ontario.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract Diabetic neuropathic pain (DNP) is a debilitating complication of diabetes that affects millions of individuals worldwide, yet its underlying molecular mechanisms remain poorly understood, and effective treatments are limited. Emerging evidence implicates methylglyoxal (MGO), a reactive glycolysis byproduct, in the development of DNP, potentially through activation of the integrated stress response (ISR). The ISR regulates mRNA translation under cellular stress and has been linked to nociceptor hyperexcitability. Our research seeks to investigate how MGO-induced ISR activation alters translational control in nociceptors, with a specific focus on the role of eIF2A in driving ISR-mediated protein synthesis that contributes to pain hypersensitivity in DNP. Specific Aim 1 will use a translational approach that integrates next-generation sequencing (TRAP-seq, Ribo- seq) in mouse and humans. Specific Aim 2 will utilize gene editing (CRISPR-Cas9), and functional assays (calcium imaging, pain behavior) in mouse, rat, and human nociceptors. Together, the aims will define conserved and species-specific mechanisms linking diabetes, ISR activation, and nociceptor dysfunction. This fellowship will provide rigorous training in molecular neuroscience, RNA sequencing, bioinformatics, and translational diabetes and pain research to ensure a strong foundation in both experimental and computational techniques. The training environment consists of collaborative research setting with access to state-of-the-art sequencing technologies, primary human DRG cultures, and established preclinical models of diabetes, offering an unparalleled opportunity to bridge mechanistic studies with clinical relevance. By investigating novel ISR-driven mechanisms underlying nociceptor dysfunction in DNP, this project aims to identify new molecular targets for objective DNP diagnosis, developing new models to study DNP, for possible new avenues for therapeutic intervention, and improving the quality of life for individuals with diabetes.

Michigan Arts and Culture Council

The Michigan Arts and Culture Council awards grants to arts organizations, artists, schools, and communities to support arts education, cultural programming, and creative sector development across Michigan.

Michigan Council for Arts & Cultural Affairs

Michigan Council for Arts & Cultural Affairs provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across MI.

OD - NIH Office of the Director

We request funds to acquire a state-of-the-art microGRID-MALDI2-timsTOF fleX imaging mass spectrometer from Bruker Daltonics to establish the Center for Single-Cell and Spatial Metabolomics & Multi-Omics (S²M²) at the University of California San Diego (UCSD). This new Center, led by a recently recruited expert in imaging mass spectrometry, will address a critical gap in lacking high-resolution spatial metabolomics infrastructure at UCSD, in San Diego, and across Southern California, and will be the first shared facility in the United States offering single-cell metabolomics. The requested instrument enables high-sensitivity, high-throughput mass spectrometry imaging at the single-cell spatial resolution, powered by MALDI-2 post-ionization, Trapped Ion Mobility Spectrometry (TIMS), and microGRID laser optics. These capabilities are essential for meeting the growing demand for spatial and single-cell omics, particularly in studies of metabolism, which is increasingly recognized as a key driver of cell identity, immune function, and disease progression. The instrument will catalyze NIH-funded research in cancer biology, aging, developmental biology, infectious diseases, drug metabolism, and tissue regeneration. The Center will leverage METASPACE, an open-source cloud platform for metabolite annotation and spatial data interpretation developed by the PI’s team and used by over 4000 scientists worldwide. By combining cutting-edge instrumentation with intuitive, accessible software, S²M² will provide a seamless workflow for biologists and clinicians, dramatically reducing the technical barrier to high-resolution spatial metabolomics. The PI brings extensive experience in directing centers, having previously founded and led two shared facilities for metabolomics and imaging mass spectrometry in Europe. With strong institutional support, a strong enthusiasm among UCSD scientists, high-end equipment, and unique software, the S²M² Center is positioned to become a regional and national leader in single-cell metabolomics. The instrument will be housed in a dedicated, fully equipped laboratory in the Biomedical Sciences Building and operated under a financially sustainable, service-oriented model. This investment will have immediate and lasting impact by enabling next-generation spatial metabolomics at UC San Diego and establishing a unique national resource for spatial and single-cell analysis in biomedical research.

NIH

Background and Innovation: Chronic Obstructive Pulmonary Disease (COPD) has reached epidemic proportions, but specific therapies do not exist. Emphysema is a major subset of COPD and is defined histopathologically as enlarged airspaces, which result in ineffective gas exchange. Aside from age, cigarette smoke (CS) exposure is one of the most common identifiable risk factors for emphysema/COPD. Our proposal addresses the current lack of effective preventatives and therapeutics in emphysema/COPD in the following ways: 1. We found that low levels of immune proteins, called Macrophage migration inhibitory factor (MIF), lead to age- or CS-related emphysema, 2. We found low MIF increases susceptibility to one of the most lethal complications of COPD—bacterial pneumonia, 3. We identified the gene-patterns, called polymorphisms, in the region of the MIF gene that controls its protein levels and now have humanized MIF mice that can be challenged with CS and bacterial infection, 4. We linked human MIF polymorphisms to susceptibility to COPD and a common bacterial infection called S. Pneumoniae and now have humanized MIF mice to perform proof-of-concept studies and 5. We developed and tested ways to restore MIF levels in the entire body and specifically in the lungs. Our main objective of this competitive renewal proposal is to define the biologic relationships between MIF genetic polymorphisms, emphysema/COPD and its lethal complication, S. pneumoniae infection, and to test the therapeutic impact of MIF augmentation in CS-induced emphysema/COPD and S. pneumoniae infection. We will use innovative, genetic mouse models and translate our findings to unique human ex vivo lung systems, which will also allow us to perform pre-clinical pharmacologic testing of our new MIF augmenters / agonists. We will identify MIF and MIF-related gene signatures that correlate with the presence/absence of a COPD/emphysema diagnosis. Significance and Impact to Veterans Healthcare: Upon completion of these studies, we will expand our basic understanding of MIF genetics in CS-induced chronic lung disease and bacterial pneumonia, thereby providing potential novel lung-targeted, personalized therapeutics. These advancements are particularly significant for Veterans' healthcare, where COPD is notably prevalent and associated with high mortality rates. COPD is a leading cause of morbidity among veterans, exacerbated by their unique risk factors, including higher rates of smoking and exposure to environmental pollutants during service. The development of personalized therapeutics, informed by both genetic and therapeutic studies, may revolutionize diagnostic and treatment paradigms for veterans. This approach aligns with the growing demand for precision medicine in Veterans' healthcare, offering a pathway to more effective, individualized care strategies that can address the complex healthcare needs of our veterans who suffer from chronic obstructive lung diseases. Path to translation/implementation: 1. Proof-of-Concept Validation: Utilizing our humanized MIF mouse models, we will first confirm the therapeutic potential of modulating MIF levels in treating CS-induced emphysema/COPD and bacterial pneumonia. These models, which mirror human MIF genetic polymorphisms, provide a robust platform for validating our hypotheses under controlled experimental conditions. 2. Pre-Clinical Testing in ex vivo Human Lung Models: By leveraging both human and mouse PCLS as well as state-of-the-art Spatial Transcriptomic technology, we will be able to translate the therapeutic potential of MIF augmentation while revealing new gene-gene and cell-cell interactions in lungs.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Type 2 diabetes mellitus (T2DM) is a chronic condition characterized by impaired blood glucose control ultimately leading to cardiovascular, renal, and cognitive dysfunction. T2DM prevalence continues to rise in the U.S., with massive health and financial consequences. Current diet and exercise recommendations often fall short in helping adults with T2DM achieve long-term glycemic control because they inadequately address common psychological barriers (such as chronic stress) that undermine adherence to lifestyle behavior change. Mindful eating and yoga have emerged as promising strategies for T2DM management by combining mindfulness practice with physical activity, dietary habits, and diabetes self-management. Both mindful eating and yoga have independently shown promise for improving glycemic control in adults with T2DM. Mindful eating may help improve emotional regulation, strengthen awareness of internal hunger and satiety cues, and promote increased consumption of nutrient-dense foods, all of which can contribute to improved blood glucose management. Similarly, yoga has shown promise for reducing stress, reducing inflammation, and indirectly supporting T2DM management by fostering healthier attitudes toward lifestyle changes. However, current research has several limitations, including a limited understanding of the mechanisms driving these effects, inconsistent use of yoga types across studies, a scarcity of studies conducted in the U.S, and few studies assessing the combined impact of mindful eating and mindful movement for adults with T2DM. Therefore, rigorous and culturally diverse research is needed to evaluate the combined impact of mindful eating and yoga on T2DM management. We propose a 12-week pilot randomized controlled trial (RCT) to assess the feasibility, acceptability, and early efficacy of a combined mindful eating and yoga intervention to lay the groundwork for a larger efficacy trial. Using a single-blind, two arm RCT, 60 adults (>18 years old) will be assigned to either: a mindful eating and mindful movement group (MEMO) or a standard of care exercise and diet group aligned with American Diabetes Association recommendations. Both groups will engage in hour-long exercise sessions 3x/week and group diet counseling sessions 1x/week. As the primary outcome, a comprehensive battery of feasibility and acceptability measures will be used to determine if a combined mindful eating and yoga program can be successfully delivered to this population. To quantify the impact of mindfulness on key health and clinical outcomes, we will use state-of-the-art measures, including biomarkers (cortisol and HgbA1c), accelerometer-measured physical activity levels, validated dietary assessments, and psychological health scales. Although this pilot study is not designed to establish definitive effects, these measures will provide valuable preliminary insights into how mindfulness delivered via mindful eating practices and yoga may influence metabolic, behavioral, and psychological outcomes in T2DM.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY This application seeks funds to purchase a MINFLUX 3D Microscope. This instrument would support nine NIH-funded users in five departments and four colleges within the Texas A&M University (TAMU) community and a group of four NIH-funded investigators at UT Southwestern Medical Center. The MINFLUX microscope would be the second major instrument in a recently established shared user facility, the Joint Microscopy Laboratory (JML), which is focused on single molecule fluorescence applications. The JML includes significant wet-lab and tissue culture space to encourage use by more distant laboratories both on campus and external to the university. MINFLUX is a relatively new state-of-the-art pointillistic imaging and particle tracking strategy that is extremely thrifty with the use of photons, requiring ~10-fold less photons than the common PALM/STORM- type pointillistic super-resolution approaches. Consequently, MINFLUX can achieve precision levels of a few nanometers on a sub-millisecond timescale within functionally active cellular systems and long single molecule trajectories in three-dimensions (3D) can be obtained using single fluorophore tags. The requested MINFLUX 3D system will enable numerous multi-color strategies combining both static imaging and molecular tracking approaches. Users will examine well-controlled in vitro systems as well as stabilized and complex cellular systems (fixed and permeabilized cells), many with an eye towards live cell investigations. The Major Users will examine fundamental and diverse cell biological and mechanistic biochemistry questions focused on nucleocytoplasmic transport, condensates, bacterial pili, nuclear mechanical stress and synapses. The Minor Users projects include structure, function and biophysical studies of mitochondrial RNA editing and kinase signaling, chemotaxis, endosomal escape, endocytic recycling, antibiotic biosynthesis, phage infection, and additional projects on condensates and synapses. The full-time technician needed to run the MINFLUX microscope will be supported by a combination of user fees and ongoing contributions from departments, colleges, Texas A&M Health, and the Vice President for Research, emphasizing the widespread importance of the new microscope capabilities to advance the capabilities and growth of current research programs. The instrument will be housed in the College of Medicine by the Department of Cell Biology and Genetics, which has donated substantial equipment and space for the nascent JML microscope facility. Altogether, the identified users have planned new research directions that are expected to ultimately require > 90% of the total accessible user time, indicating the substantial demand for both existing and newly developing projects. In total, the requested MINFLUX 3D microscope will provide substantial and fundamental infrastructural support for a wide range of projects important for understanding and improving human health.