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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.

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.

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.

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.

Mini Mart City Park

Mini Mart Art Attacks will be held from Sept 2023-April 2024 with curated monthly event series centered around local art, food, and community. All events will be free-of-cost. Each month will include: (1) a gallery exhibit showcasing a local artist, (2) a public art experience or workshop, and (3) a community meal prepared by a local chef. At the end of the series, we will curate a booklet showcasing featured artists, chefs and community members who participated throughout the project. Copies will be available for free to the community.

Mini Mart City Park

Mini Mart City Park (MMCP), located at 6525 Ellis Ave S Seattle WA, is a place for the arts, education, environmental action, and community collaboration in the Duwamish Valley. Once fully constructed, MMCP plans to advocate for creativity and public health through art exhibits, residencies, environmental action, and locally-focused programs. Phase 3 of the project is to fund the building's exterior finishes. The anticipated completion date is June 30, 2021.

Mini Mart City Park

The Mini Mart City Organization is planning a physical improvement at 6525 Ellis Ave South, to transform a former gas station into publicly accessible pocket park and arts-oriented community center in Georgetown. The main goal is to offer this space to help to prevent residential, commercial, and cultural displacement in this community by serving as a hub for community programs, gatherings, and public conversations. Phase III construction is expected to be done by the end of 2019, and they will open to the public first quarter of 2020.

OD - NIH Office of the Director

Project Summary/Abstract This proposal requests the purchase of the Miniaturized Two-Photon Microscope (Mini-2P) Imaging System from Thorlabs, Inc., a complete state-of-the-art system designed to advance neuroscience research. This lightweight, head-mounted system enables high-resolution, dual-color imaging in freely moving animals, surpassing the limitations of traditional one-photon miniscopes and benchtop two-photon microscopes. It will support immediately five Major Users with NIH-funded projects to explore brain functions, such as reward processing, adult neurogenesis, and social behavior regulation, by providing unprecedented insights into intact neuronal activity. For instance, it will allow simultaneous imaging of distinct neuronal populations in the Nucleus Accumbens during reward tasks and longitudinal tracking of hippocampal neurons during navigation. The Mini-2P will also enhance the Animal Behavior Core, supporting over 20 laboratories at the Albert Einstein College of Medicine. By facilitating studies of brain circuits in naturalistic settings, this instrument will drive discoveries in neurological disorders like addiction and autism, aligning with Einstein’s efforts in advancement of medical knowledge and practice. Institutional support, including funding and expert staffing, ensures its sustainability, fostering collaboration, training, and innovation in neuroscience research.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY This application is submitted in response to RFA-DA-26-001: SCORCH Data Mining and Functional Validation. Human immunodeficiency virus (HIV) infects non-neuronal cells in the brain, particularly microglia, which serve as reservoirs of latent infection. HIV has deleterious effects on both non-neuronal and neuronal cell function in brain regions involved in reward, emotion, and cognition. Many of these same regions, including the nucleus accumbens (NAc), also regulate the motivational properties of opioids and other drugs of abuse. Opioid use disorder (OUD) is more prevalent in people living with HIV than in the general population, and HIV and OUD reciprocally interact, with each exacerbating the severity of the other. EcoHIV is a modified HIV strain capable of infecting microglia, macrophages, and CD4+ T cells in mice, and recapitulating key pathobiological features of chronic HIV infection in humans. As part of the SCORCH consortium, we have generated single-nucleus RNA sequencing (snRNA-seq), two-dimensional (2D) single-cell spatial transcriptomic (Spatial-seq), and 3D single- cell Spatial-seq data from the NAc of control and EcoHIV-infected mice that remained drug-naïve or had a history of intravenous (IV) opioid (oxycodone) self-administration. Sequencing data were also collected from the same groups of mice that received antiretroviral therapy (ART). Here, we will mine this unique dataset to investigate the cellular and molecular mechanisms of HIV and opioid interactions in the NAc. In AIM 1, we will analyze our sequencing data to define the genetic phenotypes and spatial organizations of the medium spiny neurons (MSNs) in the NAc that undergo the most robust transcriptional remodeling in response to HIV infection alone and in combination with opioid self-administration. This analysis will enable us to distinguish between D1- and D2-expressing MSNs, identify novel subtypes, and determine their distributions within the NAc according to established (e.g., core versus shell) or novel spatial architectures. We will also integrate our mouse sequencing data with similar datasets collected from HIV-infected and drug-experienced rats, non-human primates (NHPs), and humans, available through the SCORCH-Neuroscience Multi-omics (SCORCH-NeMO) Archive. By constructing a cross-species cell atlas of the NAc, we can prioritize HIV and opioid-responsive MSN subtypes for further analyses. In AIM 2, we will employ cutting-edge circuit mapping, electrophysiological, and molecular approaches to characterize functional adaptations in the genetically defined and spatially organized MSN subtypes that exhibit the most robust transcriptional responses to HIV infection and opioid exposure. In AIM 3, we will use the CRISPR-Cas9 system to target high-priority genes dysregulated by HIV and opioids in genetically defined and spatially organized MSN subtypes in the NAc. The effects of CRISPR-mediated gene cleavage in MSNs on IV opioid self-administration and other NAc-mediated behaviors relevant to HIV/opioid interactions will be evaluated in EcoHIV-infected mice. This highly innovative research program promises to fundamentally advance our understanding of the pathobiological interactions between HIV and opioids.

Minnesota Arts Board

The Minnesota Arts Board awards grants to artists, arts organizations, schools, and communities throughout Minnesota to support artistic creation, arts education, cultural access, and the integration of arts in community life.

Minnesota State Arts Board

Minnesota State Arts Board provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across MN.

Missouri Arts Council

Missouri Arts Council provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across MO.