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NIH

Significance to VA. Disrupted sleep occurs in many conditions common in Veterans, including VA research priorities such as post-traumatic stress disorder (PTSD), substance abuse, major depression and neurodegenerative disorders. Insomnia is associated with an increased risk for suicide and increases the risk for relapse in opioid use disorder. Furthermore, disrupted sleep and abnormal sleep spindles are common in expensive, hard-to-treat conditions such as dementia and schizophrenia. Increasing evidence suggests that sleep spindles are needed for memory consolidation. Deep sleep is vital in clearing the toxic proteins which are increased by traumatic brain injury and cause neurodegeneration. Accordingly, novel strategies to promote deep restorative sleep are needed for a wide variety of disorders affecting Veterans. Cognitive treatments have utility but exert a relatively modest effect and the most widely used existing pharmacological treatments may disrupt deep restorative sleep and be habit-forming. Thus, alternative treatments are needed. Innovation and Impact. Here, in mice we evaluate for the first time whether deep restorative sleep can be enhanced through cell-type specific modulation of an important basal ganglia structure, the globus pallidus, pars externa (GPe). Our data suggest inhibition of GPe neurons which express the calcium-binding protein parvalbumin (PV+) shortens sleep latency and strongly increases the depth and consolidation of sleep. Our novel data show that another group of neurons which express the transcription factor neuronal PAS domain 1 (Npas1+) regulate sleep spindles, important in memory consolidation. Thus, pharmacological or brain stimulation strategies which inhibit GPe PV+ neurons may be a novel strategy to treat insomnia, whereas inhibition of Npas1+ neurons may promote memory consolidation. Our new data in Aim3 identify a safe natural pharmacological agent which opens potassium channels to inhibit GPe PV+ neurons and promote sleep. Specific Aims. Here, experiments focus on two major, non-overlapping neuronal-types of the GPe, PV+ and Npas1+, which make up 50 % and 30 % of GPe neurons, respectively. Aims 1 and 2 will use state-of-the- art neuromodulatory approaches in genetically-modified mice to test the effects of exciting or inhibiting these neurons on sleep. Aims 1 and 2 will also extend our approach to wild-type mice and identify the downstream neuronal targets. In Aim 3 we will test whether we can enhance sleep via systemic or local application of a safe natural compound which preferentially inhibits GPe PV+ neurons by opening potassium channels. Methodology. All aims investigate the effects of GPe manipulations on sleep and cortical electrical oscillations using electroencephalographic and electromyogram recordings in mice. Aim 1 uses chemogenetics to excite or inhibit GPe PV+ or NPas1+ neurons. Chemogenetics allows a prolonged increase or decrease in neuronal activity through the cell-type specific expression of G-protein activated receptors which respond selectively to an otherwise inert drug. Aim 2 will use closed-loop optogenetics to specifically inhibit (Aim2a) or excite (Aim2b) PV+ or Npas1+ during non-rapid-eye-movement sleep. Optogenetics allows fast and precise manipulation by applying light to neurons expressing light-activated ion channels or pumps. Aim 3 will use a pharmacological approach to inhibit GPe PV+ neurons by opening the potassium channels they express. Path to translation/implementation: Potentially the fastest translational application of this research is to use a pharmacological approach, as in Aim3, to enhance sleep by inhibiting GPe PV+ neurons via opening of the potassium channels they express. Several potassium channel openers, including the natural one we test here are safe and approved for use in humans and proposed as therapeutic agents. Another approach could be to modify existing electrical deep brain stimulation protocols or non-invasive stimulation approaches to target GPe to promote healthy sleep and daytime alertness. Ultimately, in the longer-term, we believe that cell- type specific approaches such as optogenetics or chemogenetics could be applied.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Opioid use disorder (OUD) is common among people living with HIV, and the combination produces more severe neurobehavioral impairments than either condition alone. Both HIV and opioids remodel neural circuits through inflammatory and neuromodulatory pathways, with brain region specific effects. Microglia, the resident immune cells of the brain, are central to these processes, yet it is unknown how HIV and opioid signals converge at the protein level to influence microglial function over time and across circuits. While single-cell RNA sequencing has revealed microglial heterogeneity, transcript levels often correlate poorly with protein abundance. Because proteins are the functional effectors of cellular processes, direct proteomic measurement provides a more accurate view of activity. However, bulk proteomics masks cell- type-specific responses, and targeted protein assays limit discovery of novel effectors. This project employs a state-of-the-art, cell-type-specific proteomic strategy using a Cre-dependent mutant methionyl-tRNA synthetase (MetRS*) system. This approach labels nascent proteins in microglia in vivo with the noncanonical amino acid azidonorleucine (ANL), enabling selective enrichment and mass spectrometry based profiling. It provides unprecedented temporal and spatial resolution of microglial proteomic changes across brain regions and disease stages. Using models of EcoHIV infection and fentanyl exposure, we will define distinct and overlapping microglial protein networks that emerge in each condition and during comorbidity. We hypothesize that HIV and opioids drive both unique and convergent proteomic programs in a brain region and time-specific manner, contributing to behavioral adaptations relevant to addiction and neuroimmune dysfunction. The phased R61/R33 design first validates and optimizes microglial proteomics across brain regions and labeling windows (Aim 1), then identifies EcoHIV-induced proteomic signatures in behaviorally relevant regions (Aim 2). In the R33 phase, we will map microglial proteomic dynamics across the addiction cycle in fentanyl, EcoHIV, and combined models (Aim 3). Finally, we will integrate mouse proteomic data with human single-cell RNA-seq datasets and validate high-priority targets using multiplexed imaging in both mouse and human brain tissue (Aim 4). Impact: This work will produce the first spatiotemporal atlas of microglial proteomic adaptations to HIV, opioids, and their combination. By identifying conserved molecular signatures that link microglial plasticity to behavioral outcomes, the project will yield mechanistic insight into neuroimmune dysregulation in comorbid HIV & OUD and lay the groundwork for targeted therapeutic strategies.

OD - NIH Office of the Director

PROJECT SUMMARY This application requests funds to purchase a cellenONE X1 Neo single-cell isolation and liquid dispenser system from Cellenion. The proposed instrument will be located in the Mass Spectrometry Proteomics Core at Baylor College of Medicine. The cellenONE X1 Neo is essential for establishing ultra-low-input proteomics capabilities at BCM and will be primarily used to isolate single cells and subcellular structures from clinical samples, pre-clinical patient-derived xenograft models, and various animal- and cell-based model specimens. Configured with protein sample processing workflows for bottom-up mass spectrometry, this platform will meet critical sample preparation needs for picogram- and nanogram-level starting materials, which demand extremely precise, low-volume, and contamination-free sample handling not adequately supported by our standard core protocols. Single-cell and spatial proteomics is a novel and rapidly advancing area of biomedical research with the potential to transform our understanding of cellular heterogeneity and disease mechanisms. However, despite BCM’s extensive research infrastructure, this capability is currently lacking at our institution. The addition of the cellenONE X1 Neo represents a significant leap forward, enabling our core to offer a complete, automated solution for ultra-sensitive proteomic analysis. Importantly, this instrument will leverage a recent acquisition of the Bruker timsTOF Ultra2 in the Mass Spectrometry Core – a $1.2 million investment in state-of-the-art mass spectrometry instrumentation capable of measuring ultra-small-scale proteomes. Although this Bruker timsTOF is already used for other challenging applications, the absence of a suitable single-cell preparation platform remains a critical barrier to adopting true single-cell and spatial proteomics workflows. The unifying aim of the projects supported by the cellenONE X1 Neo is to explore the molecular mechanisms driving normal physiology and disease at the level of individual cells or rare cell populations. This instrument will provide the precision, scalability, and operational robustness necessary to meet the evolving needs of our growing user base. Its integration into the Mass Spectrometry Proteomics Core aligns with BCM’s strategic plan to expand and share cutting-edge proteomics capabilities and will directly enhance research initiatives in cancer, metabolic disease, neuroscience, immunology, and beyond. The cellenONE X1 Neo will position the Core, and BCM more broadly, as a regional leader in ultra-sensitive proteomics by providing a comprehensive, accessible sample processing solution.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary/Abstract Psoriatic arthritis is a chronic and progressive inflammatory arthritis closely linked with psoriasis. Blockade of the IL-17 signaling pathway shows impressive efficacy and excellent safety for treatment of psoriasis but less so for PsA. Tissue penetrance limits the bioavailability of monoclonal antibodies to the joint and fibrocartilaginous enthesis and IL-17A signaling is diversified by local immune cells in tissues rendering IL-17A inhibition less effective. A higher dosage poses the risks of serious infections and certain types of cancer as all IL-17 inhibitors are immunosuppressive therefore to improve clinical outcomes in PsA more selective targeting is required. Herein, we have developed a novel animal model of IL-17A gene transfer where mice develop joint and skin inflammation associated with enthesitis, fingernail psoriasis and onycholysis hallmarks of PsA pathology. We will interrogate our murine model to define the early cellular and molecular pathways that dictate IL-17A-induced pathologies using state-of-the-art transgenic mice and molecular tools. Our work will uncover the pathogenic mechanisms of IL-17A and uncover novel molecular targets that can be exploited for therapeutic intervention and directly benefit PsA patients worldwide.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY / ABSTRACT Endosymbiotic events have driven the evolution of dramatic and consequential biological traits, however most known examples occurred billions of years ago, resulting in deeply integrated associations that mask early steps in the evolution of these associations. “Solar powered, sap sucking” Sacoglossan sea slugs represent a recent and incompletely established endosymbiosis in which stolen, functional chloroplasts are stored in slug tissues. Here, I propose to leverage this unique organism to understand the mechanistic basis of stolen chloroplast (kleptoplast) retention and integration into host cell physiology as a model for understanding endosymbiosis more broadly. To accomplish this, I will: (Aim 1) use organellar proteomics to identify proteins critical for establishment and maintenance of this endosymbiosis (often called “functional kleptoplasty”), (Aim 2) determine the function of those proteins using a combination of pharmacology, patch clamp experiments, and heterologous expression studies, and finally (Aim 3) expand these experiments in a comparative approach using different species of Sacoglossan slugs with different retention abilities. Thus, this study will employ rigorous methodology combining state-of-the-art sequencing technology and multi-omics approaches with physiological approaches, functional assays, and a diverse set of imaging techniques. Further, I will leverage the incredible biodiversity of sea slugs to empower a comparative approach for a comprehensive understanding of a truly unique biological phenomenon: the maintenance of functional photosynthetic chloroplasts within animal tissues. This project will take place at host institution Harvard Medical School (HMS, Cell Biology) and builds on my expertise in transcriptomics, evolutionary biology, and bioinformatics with training in new skills from my primary sponsor, Dr. Corey Allard (HMS, Cell Biology), in electrophysiology, biochemistry, and molecular techniques. I will be aided by an interdisciplinary advisory team composed of my co-sponsor, Dr. Wade Harper (HSM, Cell Biology), an expert in organelle proteomics, Dr. Steven Gygi (HMS, Cell Biology), a world leader in proteomics, and Dr. Amy Lee (HMS, Cell Biology/Dana Farber Cancer Institute), an expert in transcription and RNA biology. Investigation of functional kleptoplasty in Sacoglossan sea slugs will fill a critical gap in our understanding of the evolution of endosymbiosis and the integration of novel organelles into host cells. Completion of these aims will reveal mechanisms used by slugs for sequestration and maintenance of chloroplasts, and thus advance our understanding of the origins and functions of organelles and the fundamental processes that drive the evolution of novel traits. These insights may have broad applications in biotechnology, and could serve as a blueprint to engineer other types of cells to perform photosynthesis, or to take up different foreign cargoes for applications in agriculture, medicine, or even space travel.

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY Numerous environmental agents (hereafter, genotoxins) induce DNA lesions or create other types of barriers that stall replication forks. This can lead to replication stress, and failure to alleviate this stress and restart stalled forks can cause genome instability. Elevated replication stress and the replication-associated mutations that result from genotoxin-induced fork stalling contribute to aging, inflammation, cancer, and numerous other chronic diseases in humans. This project aims to advance understanding of the cellular responses to replication stress. One crucial aspect of the replication stress response involves replication fork reversal, a process that remod- els both the nascent and parental DNA strands to form a four-way junction structure. Fork reversal is carried out by a family of ATP-dependent translocases. Why multiple enzymes with similar activities are involved in this process is not understood. We showed that one of these translocases, HLTF, prevents a remarkably DNA dam- age-tolerant mode of replication by promoting fork reversal and preventing alternative and potentially error-prone modes of DNA synthesis. The unanticipated resilience of the replication fork to various genotoxins in HLTF’s absence may drive mutagenesis and promote the survival of damaged cells. We will investigate the cellular responses to genotoxic and oxidative damage, focusing on the mechanism of replication fork reversal and the impact of loss of fork reversal on genome stability and cell fitness. By combining molecular, biochemical, genomic and proteomic approaches, as well as state-of-the-art single-molecule ap- proaches, we will address the following broad questions: What are the functions of fork reversal and how does it occur in response to environmentally relevant forms of genotoxic damage? What are the specific functions of a central regulator of fork reversal, HLTF, in the face of oxidative and genotoxic DNA damage? Does loss of HLTF and fork reversal increase mutation (rates) in the context of environmental stressors? Our strategy will initially focus in large part on HLTF, elucidating its unique roles. As the project evolves, we will phase in further studies on other remodelers so as to understand, over the long-term, the overall fork reversal process and the unique contributions of each protein to the replication stress response. The knowledge we gain from this research will ultimately facilitate the development of new strategies that i) alleviate the pathological states observed in the absence of the replication stress response, and ii) prevent cancer cells' ability to tolerate DNA damage and develop drug resistance.

NIGMS - National Institute of General Medical Sciences

Montana State University (MSU) is the alma mater of Maurice Hilleman, the most prolific vaccine scientist of the 20th century. The Hilleman legacy is important to MSU and a point of pride in the state of Montana. Beyond the Hilleman Scholars program and the Hilleman Research Symposium, MSU prioritizes “consequential” biomedical research aimed at understanding the molecular basis of disease. This research is supported by a BSL-3 (select agent capable) laboratory, a large animal BSL-2 facility, the only contemporary cryo-electron microscope capable of high-resolution structure determination the region, state of the art confocal and chemical imaging labs, and new investments in a cell analysis core. This existing infrastructure helps support the long-term goal of this Phase 1 Center of Biomedical Research Excellence (COBRE) to establish a sustainable Center for Advanced Molecular Pathogenesis (CAMP) that fosters recruitment, development, and retention of investigators who share a common interest in translating new discoveries in pathogenesis into new treatments, vaccines, and cures. The theme of this application is intended to be broad enough to cultivate and maintain a pipeline of new faculty with diverse model systems, techniques, and scientific perspectives, while maintaining a unified research goal that focuses on understanding mechanisms and developing treatments for disease. Significantly, this application takes advantage of a talented pool of COBRE-eligible investigators in three departments from two Montana campuses and anticipates the recruitment of additional cohorts of early-stage investigators that will benefit from professional mentoring, instrumentation, and infrastructure essential to advancing biomedical excellence at Montana State University. To achieve this long-term goal, we propose three specific aims: 1) Recruit, develop, and retain a critical mass of investigators necessary to sustain a rigorous, productive, and merit-based research Center focused on Advance Molecular Pathogenesis (CAMP), 2) Improve capacities to translate basic research discoveries into tangible benefits for individuals and society, and 3) Establish core facilities that advance the aims of early-stage investigators, and simultaneously expands the biomedical research infrastructure in Montana and the surrounding IDeA-eligible states. To accomplish these aims, we propose three initial research projects, supported by two cores: The Administrative Core and the Advanced Biological Imaging and Cell Analysis Core. The rigor and feasibility of this application is enhanced by the leadership team (which includes two former COBRE investigators), the prior training and track record of our Research Project Leaders, tailormade mentorship teams, the research infrastructure supported by this award, and active engagement with world-renowned members of our advisory committee. Success of the current cohort will create a syphon, pulling new investigators into a high-priority career development program, thereby building a critical mass of investigators with the necessary momentum to sustain a unified research Center that focuses on understanding mechanisms and developing treatments for disease.

NIGMS - National Institute of General Medical Sciences

UNIVERSITY OF NORTH DAKOTA HOST PATHOGEN INTERACTIONS OVERALL SUMMARY The goal of this COBRE 3 application is to continue to sustain research in host-pathogen interactions at the University of North Dakota by providing ongoing support to host-pathogen researchers. In COBREs 1 and 2, we made significant progress towards development of a host-microbe interactions program through support of individual projects, building our core group by recruitment of immunology and microbial pathogenesis experts, and supporting faculty development through mentoring programs. We established four Cores to meet the needs of the host-pathogen interactions community and provided technical and financial support that increased the number of researchers in our community utilizing state-of-the art imaging, histology, flow cytometry, and computational approaches. In Phases 1 and 2, our COBRE Investigators and Core users made important discoveries that resulted in 106 papers published in high impact journals, and the awarding of more than $30 million in external funding from NIH grants alone. In this proposal, we seek to maintain this momentum and move our group towards sustainability through the following strategies: (1) Supporting our Cores to enable performance of cutting-edge research, transition to financial sustainability, and empower researchers through training and educational workshops; (2) Promote high- quality research, expand the reach of the group through collaborations with experts in other fields, and support innovative, cross-disciplinary research through a Pilot Project Program; (3) Promote long-term sustainability of the group through building partnerships with other IDeA state groups and cohorts through our successful seminar series and annual regional Host-Pathogen Interactions Symposium. Our long-term goal is to transition the HPI group into a sustainable, well-organized academic center which will serve as a conduit for increased interaction between investigators from multiple scientific backgrounds with a thematic interest in pursuing research on various aspects of host-microbe interactions. This center will continue attract top talent, train the next generation of scientists, and become a national hub for cutting edge esearch.

National Institute of Standards and Technology

The National Institute of Standards and Technology (NIST) Center for Nanoscale Science and Technology (CNST) is soliciting applications from eligible applicants to develop and implement with the CNST a Postdoctoral and Student Researcher and Visiting Fellow Measurement Science and Engineering Program. This program is intended to promote research, training, and practical experience in nanoscale science and technology on-site at the CNST, and to support collaboration in advancing the CNST s mission to support the development of nanotechnology through research on measurement and fabrication methods, standards and technology, and by operating a state-of-the-art nanofabrication facility.

National Institute of Standards and Technology

The National Institute of Standards and Technology (NIST) Center for Nanoscale Science and Technology (CNST) is establishing a financial assistance program for awardees to develop and implement with the CNST a Postdoctoral Researcher and Visiting Fellow Measurement Science and Engineering Program. This program is intended to promote research, training, and practical experience in nanoscale science and technology on-site at the CNST, and to advance the CNST s mission to support the development of nanotechnology through research on measurement and fabrication methods, standards and technology, and by operating a state-of-the-art nanofabrication facility, the NanoFab. The primary program objectives are: 1.To advance, through cooperative efforts with one or more universities, research consistent with the mission of NIST, and CNST specifically. See http://www.nist.gov/cnst/ and 15 U.S.C. Sec. 271 et seq. 2.To provide training for the next generation of nanotechnologists by providing recent Ph.D. recipients postdoctoral positions ( Postdoctoral Researchers ) to perform research at the CNST under the mentorship of a CNST Project Leader. The Postdoctoral Researchers must show promise as contributors to the mission of the CNST, and be selected on the basis of ability and of the relevance of the proposed work to the mission of the CNST. 3.To provide advanced training and access to the CNST s expertise and instrumentation by providing practicing scientists and engineers in the public and private sectors visiting senior research positions ( Visiting Fellows ) to perform research at the CNST in collaboration with a CNST Project Leader. The Visiting Fellows must be selected on the basis of ability and on the relevance of the proposed work to the mission of the CNST. 4.To provide Postdoctoral Researchers and Visiting Fellows under this program with professional development opportunities, including travel to relevant workshops and conferences. 5.To encourage U.S. industrial, university, and government scientists to participate in research at the CNST, either in collaboration with the CNST research program or by using the NanoFab, by providing support for travel and local expenses for participants traveling beyond a normal commuting distance to the CNST in Gaithersburg, Maryland.

National Institutes of Health

The National Institute of Neurological Disorders and Stroke (NINDS) is interested in supporting ambitious research projects to elucidate mechanisms of neurodegeneration in Alzheimer s disease-related dementias (ADRD) organized as a Center without Walls consortium. NINDS Centers without Walls are collaborative research networks that bring together diverse expertise from different institutions to tackle complex neurological problems that are not tractable by individual research projects.This program is considering using an activity code, such as the RM1, that enables interdisciplinary research consortia capable of identifying and characterizing novel ADRD mechanisms. Teams may include cross-disciplinary and cross-specialty expertise to address the complex co-pathologies, mixed etiologies, and disease heterogeneity in ADRD.This program is anticipated to support teams that can combine multiple approaches, such as state-of-the-art technologies, disease-relevant models, clinical science, and human specimens, to investigate unique disease mechanisms and identify new therapeutic targets, biomarkers, and other factors influencing ADRD susceptibility, resilience, and pathology. One awardee team would serve as a coordinating center for all awardees to facilitate recurring meetings, data harmonization and sharing, cross-site communication, and support the implementation of inter-laboratory rigor and reproducibility plans.This program is informed by key priorities from the ADRD Summit 2025, including embracing ADRD complexity and breaking down topic- and disease-based silos, and is intended to provide a mechanistic foundation for future translational and clinical ADRD research.Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. Investigators with complementary expertise in ADRD mechanisms, clinical phenotypes, and advanced technologies are encouraged to contact agency staff listed below for additional information.

National Institutes of Health

<p>The National Institute of Neurological Disorders and Stroke (NINDS) is interested in supporting ambitious research projects to elucidate mechanisms of neurodegeneration in Alzheimer’s disease-related dementias (ADRD) organized as a “Center without Walls” consortium. NINDS Centers without Walls are collaborative research networks that bring together diverse expertise from different institutions to tackle complex neurological problems that are not tractable by individual research projects.</p><p>This program is considering using an activity code, such as the RM1, that enables interdisciplinary research consortia capable of identifying and characterizing novel ADRD mechanisms. Teams may include cross-disciplinary and cross-specialty expertise to address the complex co-pathologies, mixed etiologies, and disease heterogeneity in ADRD.</p><p>This program is anticipated to support teams that can combine multiple approaches, such as state-of-the-art technologies, disease-relevant models, clinical science, and human specimens, to investigate unique disease mechanisms and identify new therapeutic targets, biomarkers, and other factors influencing ADRD susceptibility, resilience, and pathology. One awardee team would serve as a coordinating center for all awardees to facilitate recurring meetings, data harmonization and sharing, cross-site communication, and support the implementation of inter-laboratory rigor and reproducibility plans.</p><p>This program is informed by key priorities from the ADRD Summit 2025, including embracing ADRD complexity and breaking down topic- and disease-based silos, and is intended to provide a mechanistic foundation for future translational and clinical ADRD research.</p><p>Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. Investigators with complementary expertise in ADRD mechanisms, clinical phenotypes, and advanced technologies are encouraged to contact agency staff listed below for additional information.&nbsp;</p>

Central Carolina Community Foundation

Central Carolina Community Foundation ($200M in assets) supports nonprofits in SC through grants focused on education, community development, health, arts. Awards range from $2,000 to $75,000.

Life Over Violence Education Group

The Life Over Violence Education Group would like to host a festive event at 352 Martin Luther King Jr. Way August 25th, to empower youth, build relationships, and share healthy dialogue, to create positive change and life advancement in the community. The community event will be including free food, face painting, back to school supplies, poetry, music and activities for children.

Central Indiana Community Foundation

Central Indiana Community Foundation ($1.0B in assets) supports nonprofits in IN through grants focused on education, community development, arts, health. Awards range from $2,500 to $200,000.

Central Minnesota Community Foundation

Central Minnesota Community Foundation ($150M in assets) supports nonprofits in MN through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

Central New York Community Foundation

Central New York Community Foundation ($300M in assets) supports nonprofits in NY through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

European Commission - ERASMUS2027

Centres of Vocational Excellence. Call: Centres of Vocational Excellence. Programme: ERASMUS2027. Keywords: Agri-food, Agriculture, Air and water pollution control, Architecture and building, Arts, Biology, Building, Circular economy, Computer sciences - Operating systems (software development only), Craft skills, E-virtual, Education, Electricity, Electronics, Engineering and engineering trades, Entrepreneurship, Environmental protection, Food and drink processing, Foreign languages and cultures, Health, Health and welfare, Horticulture and gardening, Hotel and catering, ICT based learning, ICT's interoperability in education, Inclusion, Informal and non formal learning, Innovation in learning, teaching and assessment practices supported by digital technologies, Inter generational learning, Key competences, Life sciences, Manufacturing and processing, Medicine, Metal work, Mining and extraction, Road motor vehicla operations, Seafood biotechnology, Social Care, Social Media, Sports and leisure, Textiles, Tourism, Travel and tourism, Vocational training, aerospace and defence, construction, digitalisation, green skills, work-based learning. Open call from the EU Funding & Tenders Portal.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Autonomic dysfunction remains underdiagnosed and misunderstood but is a significant healthcare burden that affects millions of people in the United States. Autonomic disturbances are present in 40% of neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease, and other dementias and is often coupled with higher markers of cerebrovascular pathology. In this context, cerebrovascular health and autonomic function may be linked, but the connection is unknown. Additionally, little is understood about the contribution of autonomic dysfunction in tandem with drivers of cerebrovascular pathology on vascular contributions to cognitive impairment and dementia (VCID). The overarching objective of this proposal is to elucidate the link between drivers of cerebrovascular pathology and autonomic dysfunction and identify the impact on VCID biomarkers. Our preliminary data demonstrate that elevated cerebral pulsatility is associated with greater VCID biomarkers (e.g. white matter hyperintensities, WMH) in cognitively normal adults, and our published data demonstrate that adults with lower cardiovascular responses to physiological stressors are associated with greater WMH in healthy adults. Therefore, the central hypothesis is that disrupted cerebral hemodynamics will associate with impaired autonomic function, and together these contribute to greater VCID biomarkers. To test this hypothesis, I will use state-of-the-art magnetic resonance imaging (MRI) and the novel 4D flow MRI technique to measure cerebral hemodynamics (e.g., cerebral pulsatility and cerebral blood flow, CBF) in collaboration with experts in the field of MRI (e.g., Dr. Wieben, Co-sponsor). Additionally, I will use gold-standard techniques to directly measure autonomic function (e.g., sympathetic nerve activity, SNA; baroreflex sensitivity, BRS; and cardiovascular responses). Lastly, I will assess VCID neuroimaging biomarkers (e.g. WMH and cerebrovascular reactivity, CVR), and evaluate the associations between cerebral hemodynamics or autonomic function and these VCID biomarkers. Aim 1 will examine cerebral hemodynamics in middle-aged adults with and without symptoms of autonomic dysfunction. Aim 2 will determine the impact of cerebral hemodynamics and autonomic function on VCID biomarkers in middle-aged adults with and without symptoms of autonomic dysfunction. Collectively, these data will determine the link between cerebral hemodynamic and autonomic function and their contributions to brain health. The proposed work, in conjunction with the comprehensive training plan, will assist in the development of a scientific niche in the field and ensure success through the transition from a predoctoral trainee to a postdoctoral fellowship position. In addition, outcomes from this project will have broader implications for how to prevent or treat autonomic dysfunction that could also benefit brain health.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Viruses contain genetic material in DNA or RNA composed of nucleotides. For RNA, these nucleotides are A (adenine), C (cytosine), G (guanine), and U (uracil). Two nucleotides linked by a phosphate molecule, such as UA or CG, are called dinucleotides. Many RNA viruses, including flaviviruses, have evolved to mimic the low cytosine-phosphate-guanine (CG) dinucleotide content of vertebrate genomes to evade recognition by host zinc finger antiviral protein 1 (ZAP), which binds CG-rich or CG-enriched non-self RNA and targets it for degradation. Many viruses have also evolved reduced uracil-phosphate-adenine (UA) dinucleotide content to evade RNA- degrading enzymes and possibly ZAP. Enrichment of CG and UA dinucleotides in viral RNA is an emerging promising vaccine approach. In addition to vaccines, dinucleotide enrichment is an emerging approach for oncolytic viruses. A critical knowledge gap for the further rational development of safe and protective vaccines and effective oncolytic viruses is the lack of understanding of innate cellular immune responses to viruses carrying CG/UA-enriched RNA. Thus, in this project, we will study how peripheral and lymphoid dendritic cells (DCs) interact with CG-, UA-, and CG/UA-enriched viruses. Understanding interactions with DCs is significant because they are essential for initiating the early activation of inflammatory monocytes and adaptive T cell responses. Moreover, many viruses, such as flaviviruses like West Nile virus (WNV), have evolved to impair DC activation and DC-mediated stimulation of T cell antiviral responses. We will leverage characterized CG-, UA-, and CG/UA-enriched WNV variants, as well as the WNV–human peripheral DC–T cell interaction model. We will also use the conventional and ZAP knockout C57BL/6J mouse models to study interactions with lymphoid DCs. Unlike many human viruses, WNV is virulent in conventional C57BL/6J mice, which facilitates immune response studies. Classical virology and flow cytometry assays, bulk RNA-seq, and state-of-the-art single-cell RNA-seq will be used in the project. We will provide the first insights into how CG-, UA-, and CG/UA dinucleotide-enriched viruses interact with essential DC populations, and whether dinucleotide enrichment can overcome DC impairment and T cell dysfunction induced by wild-type virus infection. This project will advance the rational development of enriched vaccines and oncolytic viruses that selectively activate dinucleotide-specific beneficial immune pathways.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Antiretroviral drug therapy (ART) is the gold standard for HIV therapy for suppressing HIV infection. However, these small molecule drugs cannot eliminate the viral reservoir and thus, ART is a life-long therapy. Broadly neutralizing antibodies (bNAbs) could supplement ART and be used to reduce the viral reservoir through their Fc effector functions. While passive infusion of multiple active bNAbs can suppress viremia after ART is lifted, this strategy still requires the need for multiple infusions to maintain therapeutic concentrations of the bNAbs. We have been using adeno-associated virus (AAV) vectors to deliver HIV bNAbs, SIV bNAbs, and antibody-like inhibitors. AAV vectors provide means for long-term expression of bNAbs at concentrations capable of maintaining viral suppression via a one-time intramuscular administration. One issue that has been plaguing the field, especially in nonhuman primate models, is the development of host anti-drug antibodies and immune responses against the expressed bNAbs. We have recently demonstrated that targeting the immune checkpoint pathway is a promising target to limit the host immune response after vector administration. This work has resulted in consistent expression of two HIV bNAbs in rhesus macaques at concentrations thought to be in therapeutic range to suppress an HIV or SIV infection. Additionally, our work in developing eCD4-Ig, an antibody-like HIV entry inhibitor, has produced promising prophylaxis results in rhesus macaques against SHIV and SIV challenges. Because eCD4-Ig neutralizes all HIV-1, HIV-2, and SIV isolates and no escape mutations have been identified to date, it is a powerful inhibitor to combine with bNAbs for HIV and SIV therapy. Unlike ART, both antibodies and eCD4-Ig can kill infected cells, thus, providing a promising strategy to reduce and eliminate the viral reservoir. Therefore, we hypothesize combining AAV-delivered eCD4-Ig with antibodies would generate a unique viral reservoir upon suppression in the absence of ART, both characteristically and quantitatively. In Aim 1, we will optimize our AAV delivery strategy for multiple SIV antibodies and eCD4-Ig. In Aim 2, we will characterize and quantify the viral reservoir upon suppression when mediated by SIV bNAbs and eCD4-Ig compared to ART. In Aim 3, we will determine whether AAV-delivered SIV bNAbs and eCD4-Ig can increase the rate of viral reservoir decay compared to ART. These results would provide a foundation for AAV-delivered inhibitors as an alternative to ART and move the field closer to realizing an HIV cure.

NIMH - National Institute of Mental Health

HIV persists in central nervous system (CNS) reservoirs despite effective combination antiretroviral therapy (ART), contributing to chronic neuroinflammation and neuropathogenesis. While macrophages and microglia are known cellular reservoirs in the CNS, recent evidence suggests that infiltrating T cells also play a critical role in sustaining viral persistence. Limited access to human CNS tissues hampers our understanding of contributions of the CNS T cell reservoir in HIV neuropathogenesis. To closely examine the effects of HIV infection in the CNS, we will leverage a unique barcoded HIV system in a novel humanized mouse model to study CNS-resident viral reservoirs. Our preliminary data demonstrate that this barcoded HIV, which allows us to track and characterize virus that is being produced from different anatomic reservoirs, establishes a robust infection in both peripheral and CNS tissues, with RNA sequencing revealing upregulated type I interferon signaling and microglial activation, indicating HIV driven chronic neuroinflammation in vivo. Additionally, we have previously demonstrated in non-human primate (NHP) studies that HIV-specific chimeric antigen receptor (CAR) T cells that developed from gene modified hematopoietic stem/progenitor cells (HSPCs) can traffic to the CNS and reduce viral burden, indicating that there are ways to specifically deliver therapeutic antiviral T cells to the CNS. These findings highlight a need to define the mechanisms underlying T cell-mediated viral persistence in the CNS and to optimize CNS reservoir-targeted therapies. In these studies, we propose an integrated approach using barcoded HIV tracking, spatial transcriptomics, single-cell RNA sequencing, and integration site analysis to investigate the contributions of T cell populations in HIV persistence and inflammation in the CNS. Our central hypothesis is that T cells serve as key latent reservoirs in the CNS, promoting chronic immune activation, and that HSPC-derived CAR T cell therapy can effectively target and reduce these reservoirs. To test this hypothesis, we will: 1) Assess T cell reservoirs in the CNS during acute and chronic phase of HIV infection in humanized mice infected with barcoded HIV. 2) Investigate the contributions of T cell populations on CNS inflammation and neuropathogenesis during HIV infection. 3) Evaluate the antigen-specific T cell responses and therapeutic effects of CAR T cells on viral reservoir clearance and neuropathogenesis in the CNS. This study will provide critical insights into the role and consequences of T cell-mediated HIV persistence in the CNS and assess CAR T cells as a novel strategy for reservoir clearance and neuroinflammation reduction, advancing HIV cure strategies.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Opioid receptors not only mediate pain relief but also act as the targets of potent exogenous opioids that are devastatingly addictive and cause overdose deaths. The principal target for both analgesia and addiction of exogenous opioids is the µ-opioid receptor (µOR). While traditionally thought to be regulated exclusively by opioids, recent work from our group has detailed an unexpected layer of complexity: endogenous neuromodulators such as endocannabinoids and oxytocin – classically associated with their own independently signaling receptors that regulate mood, pain, inflammation, and social behavior – can directly work to allosterically modulate µOR signaling. This unanticipated ligand-mediated crosstalk opens an entirely new dimension in opioid receptor pharmacology and suggests that targeting these pathways could yield novel interventions for opioid use disorder (OUD) and related conditions. The central goal of this project is to elucidate, at atomic resolution, the molecular mechanisms by which endogenous neuromodulators influence µOR structure and function. We will employ state-of-the-art cryo-electron microscopy (cryoEM) approaches to determine high- resolution structures of µOR in both its active and inactive states, bound to cannabinoids and neuropeptides like oxytocin. Critically, we will advance methodological innovations in time-resolved cryoEM to directly visualize the intermediate conformational states and the full activation/inactivation pathway of the receptor as it transitions between these endpoints. This will allow us, for the first time, to construct “molecular movies” that reveal the stepwise mechanisms by which natural modulators influence receptor activation, allostery, and signaling bias. Through these detailed structural insights, we aim to identify previously unrecognized allosteric sites and intermediate states that serve as "control points" for selective pharmacological intervention. These discoveries will inform the rational design of new therapeutic strategies that harness or mimic the brain’s own modulatory systems, offering a pathway to safer, more targeted treatments for OUD, pain, and overdose. In summary, this project will not only clarify the molecular basis of opioid receptor regulation in the brain, but will also set the stage for mechanism-driven drug discovery to address the current opioid crisis and advance our broader understanding of GPCR biology.

NCI - National Cancer Institute

PROJECT SUMMARY The Fanconi anemia (FA) pathway is involved in several key processes required to maintain genome stability. It promotes the repair of DNA lesions, such as inter-strand crosslinks (ICLs) and DNA double strand breaks. It is also involved in protecting nascent DNA from degradation and preventing the accumulation of single-strand DNA (ssDNA) gaps during DNA replication. FA pathway proteins also favor the resolution of RNA-DNA hybrids (R-loops), which form as a result of transcription. Mutations in FA pathway genes cause Fanconi anemia, a genetic disorder associated with bone marrow failure, developmental abnormalities, and an increased risk of hematological malignancies and solid tumors. Mutations in FA pathway genes also predispose to hereditary breast and ovarian cancer, and they have been observed in more than a third of somatic tumors. Current treatments for cancers with FA pathway defects often involve the use of DNA crosslinking agents or PARP inhibitors. However, these treatments can lose effectiveness over time as cancer cells develop resistance. To improve therapeutic outcomes, it is therefore critical to systematically define factors required for the survival of FA pathway-deficient cancer cells. In preliminary work, we conducted high-throughput genetic interaction studies to identify dependencies of mammalian cells deficient for FA pathway genes. This work identified synthetic lethal interactions between the FA pathway and the DNA repair genes GEN1, CIP2A and RHNO1. The main goals of this proposal are to characterize mechanistically the synthetic lethal relationships between these genes and the FA pathway and determine their relevance in cancer. In particular, we propose 1) to investigate the genetic dependency of cells deficient in the FA pathway on GEN1, CIP2A and RHNO1; 2) to define the endogenous sources of replication stress that sensitize cells deficient in the FA pathway to the loss of GEN1, CIP2A and RHNO1; 3) to explore the loss of GEN1, CIP2A or RHNO1 as a cancer vulnerability in the context of FA pathway deficiency and FA gene mutations. Our approach will utilize state-of-the-art CRISPR combinatorial knockout and base editing screens, coupled with functional characterization of genetic interactions and mutations using molecular and cell biology assays. We expect that these studies will advance our understanding of the interactions of the FA pathway with other DNA damage response pathways and identify vulnerabilities that could be exploited for the development of personalized therapies for FA pathway-deficient tumors.