Dartmouth College

NIH Research Projects · FY 2026 · 2024-04

Project Summary. The filamentous fungi, or moulds, present a particularly daunting clinical challenge with high treatment failure rates and intrinsic and/or emerging multi-drug resistance. Currently, only 3 classes of antifungal drugs are utilized to treat the majority of human fungal infections. We aim to address this significant and growing human health problem by developing a nonspirocyclic piperidine series (NSP) series of small molecules with potent antifungal activity that can overcome mould specific antifungal drug resistance in the complex infection microenvironment. The NSP series was discovered using a high-throughput small molecule antifungal screen under low oxygen conditions and in the presence or absence of fluconazole with the most common mould human pathogen Aspergillus fumigatus. From this novel screen, we identified MBX-7591, a NSP family small molecule with drug-like properties that displayed potent antifungal activity that is potentiated under low oxygen conditions. MBX-7591 also potentiates the antifungal activity of fluconazole and other triazoles against A. fumigatus, which is intrinsically fluconazole resistant. The combination of MBX-7591 and voriconazole is highly active against azole resistant A. fumigatus isolates. Additional studies revealed that MBX-7591 has potent antifungal activity against multiple drug resistant mould species including agents of mucormycoses Rhizopus arrhizus and Mucor circinelloides. Pilot murine invasive pulmonary aspergillosis model studies reveal a promising safety profile and in vivo efficacy. Based on these exciting results, our premise is that MBX-7591 analogs represent a promising new generation of safe and in vivo efficacious small molecules to combat the growing emergence of drug resistant human fungal infections. In aim 1, we will utilize SAR-driven chemical optimization of the NSP series to synthesize 300 analogs with key drug-like properties such as solubility. In aim 2, we will evaluate and prioritize NSP analogs in SAR-driving in vitro assays for potency, selectivity, and ADME properties with the goal of identifying 5-10 analogs with potent MICs against A. fumigatus, R. arrhizus, and M. circinelloides. In aim 3, we will utilize genetic, biochemical, and chemical biology approaches to define the molecular target of MBX-7591 and key analogs. In aim 4, we will identify a lead NSP compound and backup based on tolerability, pharmacokinetic parameters, and efficacy in murine models of invasive mould infections. Taken together, our proposed studies will further develop an exciting novel small molecule with infection microenvironment activity against a spectrum of clinically challenging pathogenic moulds.

NIH Research Projects · FY 2025 · 2024-03

ABSTRACT Urothelial bladder cancer represents a significant global public health burden, accounting for some 200,000 deaths each year. Among the many environmental risk factors for bladder cancer, drinking water contaminated by inorganic arsenic (iAS) represents a common cause, especially among rural populations. This mechanism appears especially relevant here in the rural state of New Hampshire, which suffers from the single highest incidence of bladder cancer among the fifty states. Despite longstanding knowledge that iAs exposure represents a highly preventable cause of bladder cancer, the precise mechanism by which iAs increases bladder cancer risk remains uncertain, leading to an absence of post-exposure risk mitigation strategies. To address this issue, we now propose to develop an entirely novel zebrafish model of urinary bladder cancer, allowing us to leverage the many advantages of the zebrafish model organism including facile gene targeting and a long history of productive use in environmental toxicology research. Our group has recently demonstrated that adult zebrafish harbor a mammalian-like contractile urinary bladder, with single cell (sc) RNA-Seq identifying both basal and luminal urothelial cell types similar to those observed in mouse and human. Based on these findings, we now propose to test the following central hypotheses: First, that urothelial-specific oncogene activation combined with tp53, kdm6a and stag2 inactivation will induce zebrafish urothelial neoplasia; second, that arsenic exposure will alter the transcriptional landscape and cell composition of zebrafish bladder; and third, that a combination of oncogenic stimuli and arsenic exposure will accelerate these changes in both pre-malignant and neoplastic zebrafish urothelium. To test these hypotheses, the following Specific Aims will be pursued: 1) To examine the ability of urothelial-specific oncogene activation and tumor suppressor gene inactivation to induce neoplastic transformation in zebrafish urinary bladder; and 2) To determine the effects of iAs on transcriptional landscapes and cell composition in normal, pre-neoplastic and/or neoplastic zebrafish urinary bladder. These studies will be enabled by our broadly inter-disciplinary, multi-institutional research team comprised of experts in zebrafish cancer modeling (Leach), bladder cancer molecular genetics (Real) and arsenic toxicology and single cell transcriptional profiling (Goodale), allowing us to pursue a variety of highly innovative strategies. Together, the studies proposed in this R21 application will determine the effects of combined oncogene activation and tumor suppressor gene inactivation in zebrafish urothelium, potentially leading to a valuable new zebrafish model of urinary bladder cancer. In addition, these studies will provide the very first glimpse of how inorganic arsenic alters the transcriptional landscape of urothelial and non-urothelial cells in vivo and at single cell resolution, informing future strategies for the effective prevention of arsenic-induced bladder cancer.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY/ABSTRACT The proposed Dartmouth IMSD program, Dartmouth Leaders in Biomedical Research (DLBR), has the mission of recruiting a diverse and motivated cohort of scholars to Dartmouth’s biomedical PhD programs to train the next generation of inclusive leaders in biomedical research. Through a competitive process, DLBR will select four new funded trainees a year, with a possibility of funding renewal for a 2nd year. Once trainees conclude their DLBR funding period, they continue DLBR participation for the remainder of their graduate training. The program will be led by three outstanding program directors, all women of color, who have a strong research background and a demonstrated commitment to academic leadership, research, education, and mentorship. They have assembled an enthusiastic training faculty of 35 mentors who are committed to diversity and inclusivity and will provide extensive opportunities for cutting-edge interdisciplinary training in basic, translational, and clinical biomedical research. The DLBR program is centered around the following aims: 1. Provide enhanced academic and research training, access to support resources, and social and professional connections for incoming students from historically underrepresented groups to support their successful transition to graduate school. 2. Provide ongoing enhanced support of DLBR trainees to foster their growth as effective and independent scientists while cultivating self-efficacy, sense of belonging, and overall well-being. 3. Provide enhanced professional and leadership skill development to prepare DLBR trainees for successful leadership roles in the biomedical research workforce. The 1st aim will be accomplished during the pre- matriculation summer when DLBR trainees will engage in academic programs, a summer research rotation, orientation activities, and cohort building activities. Training goals two and three will be supported through subsequent programming and team-mentoring for the remainder of graduate training. Through courses and highly interactive workshops, trainees will practice skills in rigorous and ethical scientific inquiry, effective written and oral scientific communication, practical well-being practices, and leadership. Trainees will also network with individuals from diverse biomedical research career paths through seminars and facilitated networking. All DLBR programming will be reinforced by robust multi-tiered mentoring and intentional cohort building. To supplement their foundational expertise, all DLBR mentors will receive extensive training in effective and culturally responsive mentorship to ensure supportive and productive mentor-mentee relationships. In addition, ongoing cohort activities will foster a strong sense of community, sense of belonging, and social support network as trainees progress through their doctoral training. Measurable program objectives will be improved matriculation of underrepresented PhD trainees, research productivity, PhD completion and time to degree, number of graduates who enter and continue in biomedical research careers. DLBR will complement and expand Dartmouth’s current initiatives to support a more diverse and inclusive community.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY/ABSTRACT Even the largest lung cancer screening trial to date, the National Lung Cancer Screening Trial (NLST) is insufficient on its own to answer questions about the effectiveness of lung cancer screening in diverse clinical settings. Findings from the NLST may not generalize to new populations due to the highly selected trial population, higher levels of adherence, and screening strategies that do not reflect current practice. Claims datasets, screening registries, and prospective studies offer opportunities for evaluating lung cancer screening strategies in real-world populations, but current methods that attempt to integrate this evidence are insufficient. Standard meta-analyses and simulation models use information from multiple trials and studies, but produce estimates that do not have a clear causal interpretation for any target population. The proposed project will bridge the gap between the available data and policy relevant questions by combining diverse information and developing new methods to estimate screening strategies that have a causal interpretation in nationally representative target populations. Our long-term objective is to reduce lung cancer mortality by combining multi-source data to learn about optimal lung cancer screening strategies in real-world populations. We will take steps toward this objective by achieving the following specific aims: (1) Use information from diverse sources to transport the effect of lung cancer screening strategies from trials to nationally representative target populations; (2) Identify individuals in nationally representative target populations who are most likely to benefit from lung cancer screening, including individuals traditionally underrepresented in trials, by jointly evaluating effect heterogeneity over multiple characteristics; (3) Model adherence patterns to lung cancer screening strategies in real-world settings and use these models to assess the effects of lung cancer screening strategies under different levels of adherence in nationally representative target populations; (4) Estimate in nationally representative target populations the comparative effectiveness of lung cancer screening strategies when the strategies have not been directly compared in the same trial but have been evaluated in different trials against a common comparator; (5) Use information from diverse sources as inputs in a simulation model to compare screening strategies that differ from those used in trials, in nationally representative target populations. This project will provide new insights on the comparative effectiveness of lung cancer screening strategies. Training in cancer prevention and statistical skills will launch my career as an independent researcher in data science and epidemiology that develops causal, statistical, and simulation methods to produce evidence that will lead to improved decision-making for cancer control strategies.

NIH Research Projects · FY 2025 · 2024-01

PROJECT ABSTRACT: OVERALL We propose the Dartmouth Learning Health System (LHS) Embedded Scientist Training (E-STaR) Center, building on a long-standing partnership between Dartmouth College (DC) and Dartmouth Health (DH) and 30 years of excellence in patient-centered outcomes research (PCOR). The DH LHS, initiated in oncology and palliative care in 2019, explicitly recognizes that the collective expertise of patients, care partners, scientists, and clinical care teams is necessary to effectively implement and sustain evidence-based, goal-aligned care. Through the Center we seek to train the next generation of LHS embedded scientists to fully partner with patients and communities to meet the healthcare needs of northern New England. Three integrated Cores will work in concert to impart LHS scientists with essential knowledge for conducting rigorous and reproducible PCOR/CER and to effectively implement evidence-based practices within the LHS. This will begin with intentional recruitment and selection of a diverse group of scientists through a national call, coordinated by the Administrative Core (AC). The Research Education Core (REC) will guide the development of the scientists’ knowledge and skills related to LHS competencies and PCORI methodology standards through a tailored training plan to be carried out over 18 months with a primary mentor and mentoring team. Experiential learning will involve the design and conduct of a LHS research project with the resources of the Research and Data Analysis Core (RDAC), including the integration of resulting evidence-based practices into the LHS. An environment of inclusivity and belonging will be fostered by creating a community of practice through scientist’s participation in a Learning Collaborative designed to create a cycle of peer-to-peer learning. The Center’s specific aims are: Aim 1: To accelerate the DH LHS through the recruitment and development of a diverse group of embedded LHS scientists equipped with the knowledge and skills to transform rural healthcare with a focus on the challenge of timely access to high-quality, equitable, person-centered care in rural settings. Aim 2: To support embedded LHS scientists through tailored training, mentoring, and experiential learning and in the conduct of PCOR/CER projects designed to advance rural health equity. Aim 3: To disseminate knowledge gained within the Dartmouth LHS E-STaR Center throughout our broader communities and to evaluate the Center’s progress in advancing the DH LHS toward meeting the healthcare needs of northern New England. By growing the LHS scientist workforce, we plan to advance rural health and healthcare equity through the study and implementation of evidence-based practices designed to make timely, high quality, person-centered, goal-aligned care accessible to all.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT Cystic fibrosis (CF) is characterized by the formation of thick mucus in the lung leading to chronic infection of various pathogens that are prone to developing antibiotic tolerance. Despite effective modulator therapy (HEMT) that improves lung function and many clinical outcomes, HEMT does not eliminate chronic, antibiotic-tolerant lung infections, the major cause of morbidity and mortality in CF. Although most people with CF (pwCF) have multispecies lung infections, almost all published studies focus on single-species infection models. Thus, polymicrobial-host interactions in CF are not completely understood, especially under physiologically relevant conditions such as anoxia typical of mucus plugs. The overarching goal of our work is to use in vitro models to gain insight into how polymicrobial infections develop in pwCF. Bacterial pathogens have been shown to secrete membrane vesicles (bEVs) that diffuse through the CF mucus to deliver virulence factors such as DNA, RNA, and proteins to their targets. As recent studies have shown that the first exposure to bacterial products alters DNA methylation and gene silencing that affect subsequent exposures, our hypothesis is that pwCF develop chronic infections in part due to epigenetic changes caused by preexposure to CF pathogens that reduce the HBEC immune response to infection over time. This application aims to characterize the effects of an in vitro model of CF polymicrobial infection on human bronchial epithelial cells (HBEC) with preexposure to bEVs secreted by the common CF pathogen Staphylococcus aureus. The polymicrobial culture contains four prevalent and abundant CF pathogens: Pseudomonas aeruginosa, S. aureus, Streptococcus sanguinis, and Prevotella melanogenica. Using transcriptomic and proteomic analysis, cytokine analysis, ATAC-Seq, and DNA methylation analysis, this study aims to elucidate the host HBEC response to treatment with bEVs. This study will contribute to our understanding of host-pathogen interactions in the CF lung and potentially identify novel therapeutic targets during infection. This project will provide the applicant with a broad range of both bioinformatic and lab techniques that will provide a strong foundation for her long-term goal of becoming an academic researcher.

NIH Research Projects · FY 2026 · 2023-12

PROJECT ABSTRACT A fundamentally new approach to molecular imaging is developed here, using high energy x-rays from a widely available linear accelerator (Linac) for precise, multi-angle, multi-shaped, excitation of optical molecular probes deep within tissue via the Cherenkov light. Cherenkov Excited Luminescence Metabolic Sensing (CELMS) was developed to probe small molecule molecular tracers of pertinent tissue function in vivo, to take advantage of the highly developed Linac x-ray sources for high-resolution molecular sensing in small animals. CELMS can be used to image through 3 cm of tissue, preserving the exquisite molecular sensitivity of optical luminescence at M-nM concentrations in vivo, while achieving millimeter level spatial sampling. This combination of ultra-high molecular sensitivity, combined with deep penetrance and spatial sampling is far better than any comparable small animal modality possible today. The thin sheets of x-rays used are shaped by multi-leaf collimators and are swept over the tissue to localize the excitation volumes of Cherenkov in vivo, allowing precise knowledge of where the detected light came from. Time-resolved emission can be captured with time-gated intensified sensors for luminescence lifetime data, that we are advancing. We also advance probes for lifetime sensing of oxygen partial pressure (pO2) and tissue acidity (pH). CELMS achieves similar benefits to light-sheet fluorescence microscopy but can image through the whole body of a rat. While the diffuse optical luminescence still has to exit the body, reconstruction-based recovery can improve the localization through iterative image reconstruction, achieved with full knowledge of where the excitation beam was within the body. Most importantly, high energy x-rays are less absorbed than lower kVp x-rays, and so this can be achieved with a radiation dose as low as a CT scan. The design can implicitly allow longitudinal temporal sampling or spatial heterogeneity histogram sampling. Advanced non-toxic biocompatible probes have been uniquely developed for this application, that do not require toxicity associated with heavy metals or nanoparticles. To advance the technology for translation to other medical centers, we identify low-cost approaches that can work with any Linac, through innovations in hardware, open-source software, and suitable metabolic probes. In the hardware advancement we invent a new sensor approach to maximize capture of every possible photon per Linac pulse, thereby minimizing dose required. The techniques can be distributed with a Linac treatment plan that is completed with a delivered dose less than a diagnostic CT scan, <10 mGy. In the probes, a new version of bright-emitting, biocompatible, implanted oxygen sensors will be advanced with high potential for daily measurement in the same locations. Taken together this project will provide the tool for a fundamentally new low-cost way to image metabolic signatures of tissue that could be widely available in any academic medical center, with superior image resolution, deeper tissue penetration, and better linearity of response than is possible today.

NIH Research Projects · FY 2025 · 2023-09

Disparities in health within the U.S. are pervasive and, for some populations, widening. High-quality primary care plays an important role in the prevention, diagnosis and management of the many chronic health conditions that contribute to health disparities among older adults. Primary care in the U.S., however, is threatened. Even before 2020, the per-capita supply of primary care physicians was falling and varied dramatically by county, threatening rural and other less-advantaged communities. Little is known about how access to high-quality primary care has changed in recent years, or about the policy-, system-, or practice-level factors that are associated with better quality of primary care for older adults. These gaps in understanding have hindered our ability, as a nation, to provide the best care to older adults. This project will address this need by drawing on a unique national dataset that includes annual information on the ownership and staffing of all U.S. primary care practices from 2015–2024, linked Medicare claims data, and surveys of nationally representative samples of these practices conducted in 2017 and 2022. Work in this project will entail: Aim 1: Examine U.S. trends in access to primary care for Medicare beneficiaries in traditional Fee-for-Service and Medicare Advantage and determine how these trends varied across more and less-advantaged populations. The team will conduct repeated cross-sectional studies of access to primary and relevant subspecialty care for Medicare enrollees and how trends in access to care varied across population subgroups. Aim 2: Identify the policy-, system-, and practice-level factors associated with better processes and outcomes of care for Medicare beneficiaries, with a focus on those with fewer social and economic advantages. The team will take advantage of the substantial differences across states, delivery systems, and physician practices in the implementation of initiatives intended to improve and support primary care to apply differences-in-differences approaches to identify potentially high impact factors. Aim 3: Conduct qualitative research to deepen our understanding of the underlying barriers and facilitators to improving primary care for less advantaged populations. Under this aim, the team will conduct key informant interviews with experts on policy, primary care and the safety net to deepen our understanding of current challenges and opportunities facing safety net practices. The team will then purposively sample practices that participated in the 2022 survey that serve populations with fewer economic advantages and conduct in-depth qualitative interviews with their leaders and staff. Findings across these three aims will be triangulated to develop recommendations that can assist practice leaders, health system leaders, and policymakers in improving primary care and reducing health disparities for older adults.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY The overall goal of NIGMS-funded research in my lab is to define the molecular and cellular mechanisms that control cell size and shape. Defects in cell size and shape are associated with human diseases including cancer, so defining the underlying mechanisms can identify future therapeutic targets. We use the fission yeast S. pombe as a model system to study these fundamental processes. These rod-shaped eukaryotic cells grow by linear extension due to polarized secretion at growing cell tips, and enter mitosis at a highly reproducible size due to regulated activation of the ubiquitous cyclin-dependent kinase Cdk1. Decades of genetic screens have identified an extensive “parts list” for regulation of cell size and shape. Our current challenge is to assemble these parts into defined signaling networks that spatially control cell growth and activate Cdk1 in a size-dependent manner. For this work, we take a multidisciplinary approach that combines genetics, quantitative live-cell microscopy, phosphoproteomics, and biochemical reconstitution. In this proposal, we will address four key unanswered questions. First, how do cortical multiprotein clusters called “nodes” control fission yeast cell size at division? We discovered that nodes contain conserved cell cycle regulators including the protein kinases Cdr2, Cdr1, and Wee1, but we do not know the mechanisms of assembly or signal transduction within nodes. Second, what is the role of multiple cell cycle pathways in monitoring aspects of cell size such as volume and surface area? We will focus on the mitotic inducers Cdc25 and Cdc13/cyclin, with the goal of generating systems-level knowledge supported by mathematical modeling. Third, how do cell polarity mechanisms that function far away from the growing cell tips contribute to cell shape? We will exploit our recent discoveries that implicate RNA granules and SNARE protein clusters as novel “at-a-distance” regulators of cell polarity and shape. Fourth, how do cell size and shape influence spatial patterning of nodes in cells? We have identified cell tips, cortical anchors, and the nucleus as critical regulators of node positioning. We will combine genetic mutants with quantitative fluorescence microscopy and particle-based simulations to define the underlying design principles of this system. Based on extensive conservation of these pathways and processes between yeast and mammals, we fully expect that discoveries from our work will impact and guide future work in other organisms and biological systems.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT A fundamental question in cell biology is how cells measure and maintain their characteristic sizes. We use two systems in Drosophila development to study cell size control that provide a natural system for uncoupling growth and division: embryogenesis and oogenesis. The early embryo is an extremely large cell that undergoes rapid divisions without cell growth, while the oocyte uses polyploid nurse cells to grow to a massive size without dividing. In the embryo, the final cell size is determined by the nucleus to cytoplasm ratio (N/C ratio). The N/C ratio controls a major developmental transition known as the mid-blastula transition (MBT) where the cell cycle stops and zygotic transcription initiates. Recently, we discovered a surprising mechanism for N/C-ratio sensing in the pre-MBT embryo. Hyper-abundant maternally provided histone H3 acts as a competitive inhibitor of the DNA-damage checkpoint kinase, Chk1, to prevent cell cycle slowing. As more and more nuclei are generated by the successive divisions the pool of “free” (ie-not chromatin-incorporated) H3 is imported into the increasing numbers of nuclei and then incorporated into chromatin thereby releasing Chk1 inhibition to allow cell cycle slowing once a threshold N/C ratio is reached. In oogenesis, polyploid nurse cells generate the maternal supply of materials required for the egg and “dump” their contents into the oocyte to achieve the correct volume. Histone biogenesis appears to play a role in regulating progression through oogenesis as well, though the molecular mechanism is unclear. Over the next five years, work in this R35 MIRA proposal will: 1) interrogate the molecular mechanisms by which maternally provided H3 contributes to cell size sensing at the MBT; 2) understand how the N/C ratio affects nuclear and chromatin composition leading up to the MBT; and 3) extend the lab’s current models of cell size sensing to the growing egg chamber. These projects will further the long-term goal of understanding cell size and cell cycle control in a diverse array of tissue types and developmental timepoints. The resulting insights will expand our understanding of fundamental processes shared by most living cells but that are obscured in other model systems by the tight coupling between cell size and cell cycle progression.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY The Nadell lab studies the spatial mechanics and community dynamics of bacterial biofilms, using Vibrio cholerae, V. parahaemolyticus, Escherichia coli, and their respective bacterial and viral predators as model systems. While some marine Vibrio species cause human disease, with cholera being the most historically important, my lab does not study virulence mechanisms or bacterial pathogenesis. Rather, we use these species to understand the architectural and community dynamics of live biofilms at cellular resolution. Most bacteria produce surface-bound biofilm communities in nature, but we have strikingly little understanding of how cell-cell interactions lead to their higher order composition, architecture, and community dynamics. Since biofilm structure and composition can contribute to their role in acute and chronic infection, understanding the mechanisms controlling their structure and composition, and in particular how predatory viruses and bacteria attack biofilm- dwelling cells, may lead to novel approaches to fight clinical infections. Over the next five years we will focus on two major frontiers that have received minimal attention using cellular resolution imaging in the biofilm field thus far. First, no work thus far has examined how temperate phages interact with biofilms at high resolution; temperate phages can amplify and kill susceptible bacteria, but they can also integrate into the bacterial genome and amplify passively along with the host bacterial cell. This phage life history is widely important in nature and in host microbiota, and indeed often affects bacterial virulence. We will study in detail where and when within biofilms these temperate phages infect and kill target bacteria, and where they integrate into the host genome. Further, we will rigorously compare the propagation dynamics of temperate phages and lytic phages within biofilms to understand how these fundamentally distinct life history strategies influence phage and bacterial fitness in realistic environments. Second, the vast majority of high-resolution biofilm research has focused on biofilms grown on glass under flow of nutrient media. Many realistic environments, including those of marine Vibrio bacteria, are not this simple, with biofilms growing on topographically complex substrates, and with nutrients derived directly from the underlying surface rather than the surrounding liquid media. We will explore the consequences of these complex topographical environments by cultivating multispecies biofilms of V. cholerae and V. parahaemolyticus growing on and consuming particles of shrimp shell chitin. This system will permit us to study how growth in a multispecies context on naturalistic substrates influences community architecture and dynamics. Lastly, we will rigorously test how the realistic chitin environment influences the ability of a ubiquitous bacterial predator, Bdellovibrio bacteriovorus, is able to attack and kill Vibrio prey within single and multispecies biofilms. Our research will expand along two important new frontiers, both of which will yield insight into how predatory viral and bacterial species kill prey bacteria dwelling in otherwise protected biofilms.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Continued support is requested for a multidisciplinary Dartmouth Training Program in Quantitative Cancer Research (TQCR). The TQCR Program seeks to provide cross-training in quantitative, computational, and biomedical sciences to prepare students for the emergent cancer research landscape that is increasingly characterized by complex problems, big data, and multidisciplinary teams. At Dartmouth, the TQCR Program will enlist graduate student trainees from different academic backgrounds, including computer science, mathematics, biology, chemistry, and engineering who are committed to cancer-centered research activities with a strong quantitative component. These graduate student candidates for TQCR support will be recruited broadly from cancer-focused research laboratories across four graduate programs at Dartmouth: The Geisel School of Medicine’s Molecular & Cellular Biology and Quantitative Biomedical Sciences PhD Programs, The Thayer School of Engineering’s PhD program, and The School of Arts and Sciences Computer Science PhD Program. Faculty mentors include quantitative scientists with significant extramural funding and a strong track records of graduate training experience and biomedical research. Research areas of the faculty include quantitative methodology and scientific applications in bioinformatics, biostatistics, computer science, computational biology, genomics, and epidemiology. Selected TQCR students will engage in a cancer-specific, quantitative curriculum that includes courses in computer science, bioinformatics, biostatistics, epidemiology, cancer biology and integrative biomedical sciences, exposing them to both interdisciplinary research and quantitative methodology development over the course of a 2-year fellowship period. This reflects our institution’s long history of exceptionally strong cancer research and clinical programs, largely based on the success of our comprehensive, NCI-designated Norris Cotton Cancer Center. It is our vision that the next generation of quantitative researchers requires comprehensive interdisciplinary training to contribute meaningfully to future progress in understanding, preventing, and treating cancer.

NIH Research Projects · FY 2025 · 2023-08

The cell cortex underlies essential cellular functions, including cell shape changes that facilitate cell division. Comprised of a meshwork of filamentous actin (F-actin) and the plasma membrane, the cortex is remodeled during cytokinesis, physically dividing the cell in two. Recent work has shown that prior to large-scale remodeling, the cortex is also dynamically patterned with coherent subcellular waves of the small GTPase RhoA and F-actin, a phenomenon termed “cortical excitability”. In developing embryos, these waves appear over the entire surface of the cell and then feed into the cytokinetic furrow as cell division progresses. Investigating the mechanisms that support and regulate cortical patterning has been greatly improved by the development of an “artificial cortex”, made from supported lipid bilayers (SLBs) and Xenopus egg extract, which successfully reconstitutes active Rho and F-actin dynamics in a cell-free system. Like in vivo cortical excitability, patterning in the artificial cortex depends on Rho activity and F-actin polymerization. This novel, synthetic approach to investigating cortical patterning is an ideal system for systematically examining the role of individual factors (such as upstream GTPase regulators, membrane composition and fluidity, cell cycle state) in regulating cortical dynamics. Using the artificial cortex as a model for cortical patterning, this proposal seeks to understand how cortical pattern formation is regulated and how patterning remodels the cell cortex to perform essential functions like cytokinesis. This system will enable us to bridge the biochemical and biophysical principles that drive pattern formation in vitro to the molecular mechanisms that drive patterning in cells. The primary goals of this project will be to investigate the factors that promote cortical wave formation (Aim 1), cytoskeletal remodeling at the cortex (Aim 2), and the role of cortical patterning in supporting successful cell division (Aim 3). This project will build on the findings from the K99 phase of the award, including the observation that SLB composition modulates the behavior and dynamics of excitable waves in the artificial cortex. As modifying membrane composition is difficult in vivo, this result highlights the importance of a synthetic system for dissecting the contributions of individual components, such as the membrane, to self-organized patterning. The work will expand our knowledge of the molecular regulation of the cortex underlying the emergence of cortical excitability, and the role of dynamic patterning in cell division.

NIH Research Projects · FY 2024 · 2023-08

Coronaviruses are enveloped positive-sense RNA viruses. Over the last two decades, coronaviruses have led to severe respiratory infections in humans. Most recently, SARS-CoV-2 led to a global pandemic and resulted in more than 6.5 million deaths globally since December 2019. We currently lack a sufficiently broad set of antiviral drugs targeting different aspects of coronavirus replication. Therefore, developing new antiviral drugs targeting currently untargeted aspects of coronavirus replication may help reduce the mortality of future coronavirus infections. As such, it is critical to understand the molecular mechanisms of many different aspects of coronavirus replication as this will help to determine which aspects of viral replication may be useful targets for the development of new antiviral drugs. One aspect of coronavirus replication that is not well understood is the mechanisms by which coronaviruses remodel host cell membranes. Once coronaviruses infect host cells, a set of nonstructural proteins (nsps) are produced from the viral RNA. Three of these nsps, nsp3, nsp4 and nsp6, are integral membrane proteins that remodel host cell membranes to generate double-membrane vesicles (DMVs) from the endoplasmic reticulum (ER). These DMVs serve as the assembly sites for the replication and transcription complexes that are critical to producing viral RNA. In addition, DMVs have been shown to contain viral RNA further highlighting the critical role of DMVs in viral RNA production. While it is clear that membrane remodeling by coronaviruses is essential for their replication, we currently lack an understanding of the molecular mechanisms by which coronaviruses remodel host cell membranes to generate DMVs. One major reason for our limited understanding of this process, is that no studies have investigated the structure and function of the membrane-spanning regions of nsp3, nsp4 and nsp6 using purified proteins. As such, we will purify nsp3, nsp4 and nsp6 for structural studies using cryo-EM and for biochemical investigations using model membranes including liposomes and giant unilamellar vesicles. Importantly, this will work will not only provide new insight into the mechanisms of coronavirus replication, but it will also help reveal if membrane remodeling by coronaviruses may be a useful target for the development of future antiviral drugs.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT The fetal/neonatal period represents a unique period of vulnerability to viral infections. While Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically non life-threatening infections among healthy adults, they are among the most consequential viral infections of early life. HSV infection during parturition or the early postnatal period results in disseminated disease or encephalitis in up to 50% of infected newbowns. Without treatment, mortality is high and an estimated 70% of surviving infants with central nervous system (CNS) involvement suffer long-term neurodevelopmental sequelae despite aggressive treatment with acyclovir. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided by the maternal immune system in the form of transferred antibodies (Ab). For HSV, maternal Ab seropositivity, resulting in placental transfer of Ab capable of directly neutralizing virus and eliciting the diverse effector functions of the innate immune system, is associated with dramatically decreased risk of nHSV. There is no currently approved HSV vaccine whereby maternal Abs could be induced among seronegative mothers. As an alternative, our previous work has demonstrated that maternal Ab readily accesses neural tissues of the fetus and is sufficient to prevent nHSV. Preliminary data now demonstrate a novel mouse model system whereby we can model not only mortality and viral burden, but also behavioral pathologies that are frequent and lifelong in humans following nHSV. The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies for nHSV infections will benefit from careful in vivo and in vitro evaluation of antibody mechanism(s) of action. Presently, there is a critical gap in knowledge of the mechanisms whereby Ab-based interventions provide benefit in the context of nHSV infection, and how these interventions might be optimized in order to best prevent this devastating disease. Our objective is to define and refine the means by which monoclonal antibodies (mAbs) can be used to prevent or reduce nHSV morbidity and mortality. We hypothesize that while Ab effector functions contribute to direct neutralization activity, they are modulated by the viral Fc Receptor (vFcR), glycoprotein E (gE/gI complex). Guided by strong preliminary data, the project goals will be achieved though completion of two Specific Aims: 1) Define the mechanism(s) of action of mAbs that prevent nHSV, and 2) Define the role of the viral Fc receptor (gE/gI) in influencing antiviral mAb activity.

NIH Research Projects · FY 2026 · 2023-08

Project Summary Human sensory systems cannot process all available inputs in a structured and meaningful way. Thus, selecting relevant information and filtering out irrelevant and distracting information is critical to survive and thrive. Decades of research on selective attention have investigated the neural mechanisms underlying the ability to focus processing resources on relevant information, demonstrating that processing of information within the focus of attention is enhanced. Much less clear is how task-irrelevant and distracting information is effectively ignored, albeit major theories of attention proposing that efficient filtering of irrelevant information is essential for many aspects of higher-level cognition. Thus, there is a critical need to identify the mechanisms that support the effective ignoring of distracting information. Without such knowledge, models of attention are incomplete, and it will remain difficult to help people avoid distractions in everyday lives. This proposal aims to identify the cortical processes involved in effective distractor suppression, focusing on two modes of attention: Experience-based attention, where based on statistical regularities in the environment processing resources are biased towards or away from relevant or irrelevant information, respectively, and volitional attention, where processing resources are allocated towards relevant or withdrawn from irrelevant information based on an individual’s intentions and explicit task goals. Recent theories of cortical information processing indicate the importance of dissociating between these two types of attention because they each influence information processing in distinct ways. Here, we test the hypothesis that experience-based attention induced via statistical regularities will be more effective relative to volitional attention when ignoring distracting information. Our approach will combine psychophysics, electrophysiological methods (EEG) and computational modeling to determine how experience and intentions influence the temporal dynamics of cortical information processing and how they shape the quality of the perceptual representations of to-be-ignored inputs. Critically, these neural measures will be directly linked to behavioral performance with the goal to identify the neural mechanisms responsible for successful distractor ignoring. Collectively, this work will provide key insights into how different modes of attentional control processes interact to shape perception and behavior, and will more broadly test general models of attention and cognitive control. Furthermore, the results of this proposal have the potential to help support people’s abilities to reduce distraction in everyday tasks, such as driving and at the workplace, and elucidate on why certain populations have particular difficulties in avoiding distractions, thereby enabling more targeted diagnoses and interventions in clinical settings.

NIH Research Projects · FY 2026 · 2023-07

Revised Abstract Section ABSTRACT Although women with disabilities experience pregnancy at the same rate as women without disabilities, they face disproportionately higher rates of adverse outcomes including pregnancy, labor and delivery complications, severe maternal morbidity, maternal death, preterm birth, stillbirth, low birth weight, and infant mortality rates. Additionally, there is limited information about the extent of demographic differences in maternal and newborn health outcomes among those who are disabled,. Developing effective interventions to eliminate demographic differences in adverse outcomes among women with disabilities requires a comprehensive understanding of the relationships between these multiple levels of risk and associated birth outcomes. This project aims to fill this research gap using linked maternal-infant Medicaid claims, and birth and death certificate data files. Three research aims are proposed. Aim 1 focuses on the magnitude of demographic differences in severe maternal morbidity, cesarean delivery, low birthweight, small for gestational age, and preterm birth among women with disability; Aim 2 evaluates maternal and infant outcomes by the type and timing of Medicaid program enrollment and includes analysis such as having a severe maternal morbidity and extended hospitalization after giving birth among women with disabilities; and Aim 3 evaluates the association between Medicaid program type and receipt of guideline concordant prenatal care among women with disabilities compared to those without disabilities as a quality measure for maternal-infant health. The proposed aims are supported by the PI’s career training goals, which include developing expertise in 1) using Medicaid claims data to identify disability and produce measures of adverse birth outcomes according to variation in the disability variable,, 2) identifying timing of enrollment and Medicaid program type for women with disabilities, and 3) developing skills in measuring quality of care received by women with disabilities when compared to those without disabilities. The proposed project supports the PI’s long-term career goal to become an independent investigator of maternal and newborn health outcomes in the U.S., with a particular emphasis on identifying and addressing care among high need populations using rigorous methodologies. Career development will include a series of formal courses, training workshops, and directed readings that will be completed with faculty at Dartmouth and other institutions over the first three years with additional topics covered as needed in the subsequent years. Attendance at conferences and related workshops will also be added to stay informed of current developments in the field. The award will be followed with a Research Project Grant (R01) to develop and test an intervention to improve outcomes among those who experience preventable maternal and infant morbidity and mortality in the U.S.

NIH Research Projects · FY 2024 · 2023-07

ABSTRACT The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies will benefit from careful evaluation of the full range of potentially protective or harmful antiviral antibody responses throughout all stages of preclinical testing. Small animal models are often used to assess antibody- based interventions to provide sterilizing immunity, but these models may also hold value for studying pathology and mechanisms of protection beyond neutralization. At present, ferrets (Mustela putorius furo) and Syrian hamsters (Mesocricetus auratus) are thought to be good small-animal models for diverse respiratory pathogens as both support infection, manifest disease, and transmit virus. To optimally use these models, there is a critical need to understand the suitability and/or shortfalls of ferrets and hamsters in recapitulating antibody effector functions that affect human clinical outcomes—requiring basic research into the genetic diversity, expression patterns, and functional profiles of both antibodies as well as Fc receptors in these animals. The goal of this project is to perform initial biophysical and functional Fc and FcR profiling in ferrets and Syrian hamsters to elucidate key variables that impact species-specific Fc-FcR-dependent effector functions. Achieving this goal is a prerequisite for optimal translation of insights gained from emerging protective and therapeutic small-animal studies to the clinic and to best prioritize strategies for human clinical trials. Guided by strong preliminary data, and using a combination of gold-standard and state-of-the art approaches, the project goal will be achieved though completion of two Specific Aims: 1) Define the biophysical interactions between FcR and IgG that determine effector functions in ferrets and Syrian hamsters, 2) Develop novel cell lines and assays for evaluating ferret and hamster Fc-mediated antibody effector functions in vitro. The data and results obtained by completing the aims of this proposal will be significant and innovative because they will generate knowledge that will identify the antibody and FcR interactions capable of tuning immune response towards potent antiviral activity versus promoting pathological inflammation in ferrets and hamsters. This knowledge will provide a roadmap for effective translation of studies performed in these small animals, often used to model respiratory pathogens, to outcomes in human trials.

NIH Research Projects · FY 2025 · 2023-06

Project Abstract Oxygen sensing with high precision & high spatial localization can provide new insights into the action and effects of ultra-high dose rate (UHDR) radiation therapy (RT), known as FLASH-RT. When compared to RT delivered at conventional dose rates (C-RT), FLASH-RT has been shown to inflict lower radiobiological damage to normal tissues while still preserving the same tumor killing efficacy. This enhanced selectivity has become known as the ‘FLASH’ effect. Oxygen (O2) has been suggested to underpin the FLASH effect, with several theories centered on increased consumption of oxygen upon application of UHDR radiation. However, our in vitro and in vivo oxygen measurements using the phosphorescence quenching method were the first to show that compared to C-RT, FLASH-RT leads not to higher, but actually lower O2 consumption per unit radiation dose. Additionally, we have been the first to establish that the oxygen consumption rate during FLASH-RT is dependent upon the baseline oxygen level within tissue, indicating that the oxygen fixation effect may be oxygen dependent. Based on these results, we hypothesize that the FLASH effect originates not from fast depletion of oxygen and radiobiological hypoxia, but rather from a dose rate dependent oxygen enhancement ratio (OER) from differences in oxygen consumption and damage fixation between FLASH-RT vs C-RT. This original hypothesis can be tested only with accurate measurement of the acute change in oxygen partial pressure (pO2), as an indirect biomarker of the oxygen fixation happening. If this is via variation in peroxyl formation, measurement of pO2 is an ideal surrogate of changes in DNA damage from variations in dose rate delivery parameters. In this project we will develop a unique high-resolution O2 imaging method to track and optimize the FLASH efficacy by combining phosphorescence quenching oximetry in vivo with Cherenkov Excited Luminescence Imaging (CELI) to dynamically quantify oxygen in tissues with spatial resolution of ~1 mm. In CELI, X-ray beams of RT generate localized optical field, which excites phosphorescence deep within tissues, and the phosphorescence, imaged with external detectors, reflects tissue oxygenation. This work will pioneer a new approach to oxygen measurements in RT and will provide mechanistic insight into FLASH radiochemistry with the important potential to optimize the radiobiological efficacy of FLASH-RT. The teams and resources at Wisconsin, Dartmouth and UPenn are unparalleled in their experimental potential for this project, and the work will provide fundamentally new capabilities in guidance of RT, with guidance by key consultants. The components of our work have been based upon high impact publication of original in vivo data with both electrons and protons. The fundamental insights that can be gained here are very timely, as the search for the origins of the FLASH effect in normal tissue is happening now. As we find ways to understand the mechanisms, that can help us optimize its effect, and test the dose rate beam delivery and oxygenation conditions for tissues that lead to its optimization.

NIH Research Projects · FY 2026 · 2023-06

Human Cytomegalovirus (HCMV) is a double-stranded DNA virus that establishes life-long infection in the human host. The overarching objective of our work is to define critical virus-host interactions important for virus replication and latency, which provide targets for antiviral strategies aimed at limiting viral pathogenesis. HCMV encodes a single DNA polymerase (UL54). As herpesviruses encode their own DNA polymerase, it has been broadly presumed that they do not require host polymerases for the replication of their genomes. However, herpesvirus genomes are complex with high-GC content and repeat sequences that constrain the B-family DNA polymerases, such as UL54. Through our collaborative effort, we demonstrated a striking role for specialized host translesion polymerases (TLS pols) in HCMV genome replication and stability. TLS pols function in lesion bypass at the replication fork or in single-stranded DNA gap filling or homology-directed repair that occurs post-synthesis (behind the fork). TLS pols also maintain fragile site stability during unperturbed DNA synthesis. TLS pols include the Y-family polymerases eta (h), iota (i), kappa (k) and Rev 1, as well as the error-prone, B-family polymerase zeta (z). Strikingly, we found that Y-family TLS pols (h,i,k, and Rev1) and pol z are important to maintain HCMV genome stability. Further, our results indicate that pols h, i, and k generate single nucleotide variants across the viral genome. These findings indicate important roles for host TLS pols in ensuring viral genomic integrity and potentially in generating viral genome diversity. We also found that depletion of TLS pols differentially impacts viral genome synthesis and replication. Defining how HCMV maintains genomic stability and the significance of host TLS pols and DNA damage repair (DDR) pathways on the viral lifecycle is important for understanding mechanisms of virus replication and latency. Further, exciting new data indicates a role for host TLS pols in the evolution of resistance to nucleoside antiviral therapies, such as ganciclovir. We hypothesize that HCMV actively recruits TLS pols and coopts corresponding DDR pathways to maintain genome integrity and regulate viral replication and latency. Aim 1 will determine the mechanisms by which HCMV recruits host TLS pols and other DDR repair factors to viral replication compartments and the subdomains in which they function. Aim 2 will define the mechanisms by which host TLS pols and other DDR repair factors act on viral sequences to ensure genome stability and contribute to antiviral resistance. Aim 3 will determine the significance of host DDR pathways to viral latency. These aims are driven by our published work and exciting preliminary data identifying virus-host interactions that control host TLS pols and DDR pathways. Our multi-PI collaborative work establishes the importance of host TLS pols for the stability and diversity of viral genomes and would not be possible without the combined expertise of Drs. Goodrum and Bosco. Further, this study offers the unique possibility of illuminating new insights into the biology of TLS pols in human cells using the HCMV genome as a model system.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT Unlike liquid cancers, current CAR T cell immunotherapies have little effect against solid cancers, largely due to the immunosuppressive nature of the tumor microenvironment. The race between administered CAR T cells and tumor associated cells to kill off and/or neutralize the other is tipped heavily in favor of the tumor. Heterogeneous tumors or tumors able to shed or downregulate CAR-targeted antigens can also escape elimination by functional CAR T cell effectors. We recently found that CAR T cells delivery of dual cytokines can enlist and activate endogenous T cells, NK cells and myeloid cells to mount an effective anti-tumor immune response. Further investigation revealed that perforin and IFNγ are dispensable in CAR T cells, supporting an accessory role for CAR T cells in mobilizing endogenous immune cells to ultimately control tumor growth. CAR T cell-mediated dual cytokine delivery was effective in controlling tumor growth with 3 different CAR T cell constructs and 4 in vivo tumor models: primary and metastatic melanoma and primary colon cell carcinoma mouse models, and importantly was impervious to antigen loss. This suggests that the dual cytokine platform has potential for universal application against multiple solid tumor types. In this application, we hypothesize that CAR T cell delivery of dual cytokines has broad application because it counteracts immunosuppressive innate and adaptive immune cells to elicit a broad endogenous anti-tumor response independent of CAR effector potential. We will test this hypothesis by identifying CAR T cell survival and distribution dynamics (Aim 1), identify the common and tumor-specific changes in immunosuppressive, immunostimulatory and effector leukocyte populations isolated from poorly and strongly immunogenic tumors pre- and post-CAR cytokine treatment (Aim 2), and determine their roles in activating endogenous tumor immunity (Aim 3). The cellular and mechanisms identified will support further improvement and clinical translation of the Super2+IL-33 platform with various CAR targeting constructs for CAR T cell therapies for solid tumors.

NIH Research Projects · FY 2026 · 2023-05

The field of epidemiology has gained increasing prominence in the research community and became a household word in 2020. Epidemiology provides the tools to uncover the underlying causes of human illness and to, in turn, inform clinical practice and preventive strategies, advise policy and regulatory actions, and move scientific advancements forward. In Phases I and II, our Centers of Biomedical Research Excellence (COBRE) Center for Molecular Epidemiology at Dartmouth has effectively advanced research in the field. As the only Center for molecular epidemiology in northern New England and one of the only COBRE programs with this focus nationally, we have successfully recruited and mentored the next generation of independent early career investigators. We further supported established investigators to enlarge their research programs, form new collaborations and integrate the latest biomedical discoveries, innovations, and methods. In doing so, we dramatically grew our research productivity and grant portfolio, as evidenced by the steep rise in the number of publications, presentations, and grants awarded since the inception of our COBRE Center. As part of achieving sustainability, we formed a new Department of Epidemiology and developed innovative cross- disciplinary training grants. Our cohesive Center brings together talented investigators focusing on 1) applying new scientific discoveries and technologies to address major human health concerns, 2) identifying early indicators of disease pathogenesis, and 3) exploring common pathways of disease etiology and progression in human populations. In this Phase III application, we will progress our molecular epidemiology research infrastructure forward to full independence and sustainability. Specifically, we will 1) evolve a state-of-the-art Biorepository and Biospecimen Resource Facility Core that supplies the critical services responsive to the ongoing and future needs of biomedical scientists, 2) expand the pipeline of talented, molecular epidemiologists, and provide the requisite mentorship, career development, and research resources to cultivate cutting-edge research and make investigators competitive for NIH funding, and 3) enhance the governance structure, implementation approaches, stakeholder engagement, and evaluation that will strengthen our Center’s impact, promote its strategic vision, and forge ties with regional and national partners. Our success in Phases I and II, combined with strong institutional support, positions us to serve as a vital resource in molecular epidemiology for Northern New England, for COBRE and IDeA Networks of Biomedical Research Excellence (INBRE) programs, and more broadly.

NIH Research Projects · FY 2026 · 2023-05

Project Summary / Abstract Systemic lupus erythematosus (SLE, lupus) is a multi-organ autoimmune disease with 5-10% mortality in 10 years. Skin is severely affected by this disease and sensitivity to ultraviolet (UV) sunlight rays affects up to 80% of patients. The immunologic mechanisms involved in cutaneous lupus (CLE) remain poorly understood. In particular, the role of different types of T cells, highly prevalent lymphocytes in CLE skin, is unknown. The overall objectives in this proposal are: (i) to profile and determine the function of MAIT cells in CLE in relation to the skin microbiome and (ii) to define the role of MAIT cells in lupus skin disease and photosensitive responses in vivo. The central hypothesis is that activation of MAIT cells, influenced by preferential expansion of riboflavin-producing bacteria, mediates skin pathogenesis in CLE. The rationale for this project stems from the gap in the knowledge of how the altered microbiome in lupus skin impacts immune activation, and specifically MAIT cells, and leads to tissue damage. The central hypothesis will be tested by pursuing two specific aims: 1 Define how skin microbiome shapes MAIT cell function in CLE patients and 2) Establish how lupus-specific interactions between skin microbiota and MAIT cells mediate cutaneous lupus in vivo. Under the first aim, MAIT cells from lupus skin (lesional and unaffected) will be evaluated for quantity, heterogeneity, transcriptomic signatures, and TCR usage (relative to healthy skin) and these findings analyzed in relation to the abundance of microbial communities and riboflavin gene expression. For the second aim, the role of MAIT cells in the development of lupus skin disease will be evaluated in Mrl-lpr mice deficient in MAIT cells (Mrl.lprMR1-/-). This new murine strain will be used to investigate how dermal association with riboflavin or Staphylococcus bacteria influences MAIT cell function in spontaneous and UV light- accelerated CLE in vivo. The research proposed in this application is innovative because it will generate a novel mechanism of lupus skin disease and interrogate a T cell population reported to have inflammatory properties in other skin disease but has not yet been studied in CLE. The proposed research is significant because it is expected to provide a strong scientific rationale to address the imbalance in lupus skin microbiome and/or modulate MAIT cells for therapeutic purposes in lupus skin disease.

NIH Research Projects · FY 2026 · 2023-04

Project Abstract One long-standing puzzle in neuroscience is how scene perception and spatial memory systems – which are topographically distinct in the brain – interface to enable memory-guided visual behavior. In the context of scene perception, two crucial knowledge gaps remain. First, how does visuospatial memory of the local environment facilitate ongoing scene perception? Second, what are the neural underpinnings of memory-guided scene perception? The current project will tackle these questions by combining head-mounted virtual reality (VR), eye-tracking, and fine-grained within-subject fMRI. We will teach participants immersive, real-world environments and test how memory-guided scene processing is implemented in the brain and behavior. In doing so, we will advance a new mechanistic hypothesis as to the neural basis of memory-based predictive coding for scene processing. Together, this project will produce fundamental knowledge about how stored knowledge about the world influences ongoing perception during naturalistic visual experience, and how the brain accomplishes memory-guided visual behaviors like navigation. The resulting knowledge promises impact for our numerous health conditions such as Alzheimer’s, dementia, macular degeneration, cortical visual impairments, and healthy aging, in which both the visual behaviors and brain regions investigated here are implicated.

Fonds de recherche du Québec – Nature et technologies · FY 2023-2024 · 2023-04

Volet: Bourses de maîtrise en recherche; Domaine: Nature et interactions de la matière; Objet: Stellaire; Objet: Instruments; Application: Sciences et technologies; Application: Fondements et avancement des connaissances; Mots-clés: POPULATION SYNTHESIS, INTERACTING BINARY STARS, COMPUTATIONAL STELLAR ASTROPHYSICS, APPLIED DATA SCIENCE IN ASTROPHYSICS, COMPUTATIONAL MODELING, OBSERVATIONAL ASTRONOMY