Boston College

NIH Research Projects · FY 2025 · 2022-08

Project Summary Episodic memory involves the construction of a complex mental representation that includes key features of an event (i.e., its people, objects, and places) and their relationships with one another. This process has been reliably associated with activity in a core network of posterior medial (PM) brain regions, including areas in medial temporal, medial parietal, and lateral parietal cortex. Yet much remains unknown about how these brain regions contribute to the specificity with which distinct event features are bound and recalled. Past investigations of memory specificity have largely focused on the contributions of individual brain regions, such as the hippocampus and lateral parietal cortex. However, recent evidence suggests that memory specificity may be explained, in part, by functional interactions among brain regions, including those in the PM network. The overarching goal of this proposal is to investigate the brain network interactions predicting the multidimensional quality of episodic memory, focusing on how distinct event features are bound into memory and the specificity with which they are represented. Our central hypothesis is that there are separable pathways through the PM network that maintain the general relational structure and specific details of an event, and that these pathways must interact to embed specific details into event memories. We will test this hypothesis by leveraging the complementary strengths of functional magnetic resonance imaging (fMRI), transcranial magnetic stimulation (TMS), and cognitive experimental design. First, we will examine variability in memory binding and specificity across events, using analytic methods to predict memory quality based on brain network interactions during encoding and retrieval (Aim 1). Second, we will test the causal role of PM network interactions in episodic memory, using a combined TMS and fMRI design to identify post-stimulation network changes and their impact on memory quality (Aim 2). Finally, we will investigate individual differences in episodic memory quality, testing whether they can be explained by differences in PM network recruitment and organization (Aim 3). The proposed research advances a novel framework for understanding the interactive pathways supporting episodic memory, with the potential to significantly transform our understanding of the brain mechanisms supporting memory for complex events. Furthermore, by building a model linking episodic memory quality to specific patterns of network activity and communication, we will be better equipped to understand the mechanisms underlying changes in memory binding and specificity often associated with psychiatric and neurological disorders.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Research into cognitive impairments and Alzheimer’s disease and related dementias (ADRD) suggests that exposure to enriching or stimulating social contexts – i.e., social complexity – may slow age-related cognitive decline and delay the onset or progression of ADRD. Most research in this area has considered how social complexity in either the proximal (e.g., social network, social activities) or distal (e.g., neighborhood) contexts shape cognition. Additionally, prior research on social complexity and cognition is conducted largely separately from existing physiological frameworks for understanding cognitive aging and ADRD. Through this K01, Dr. Alyssa Goldman will integrate existing research on the roles of sensory systems and inflammation in shaping cognitive decline and ADRD, and examine how these associations are informed by changes in both proximal and distal social complexity over time. Dr. Goldman’s long-term goal is to lead a social science research program that uses innovative approaches to better understand the social pathways of cognitive functioning and ADRD. The K01 Award will support this goal by extending her prior training as a sociologist, developing her understanding of and skills in: (1) the physiology of cognitive aging, ADRD, sensory functioning, and inflammation, (2) the objective assessment of cognition, sensory functioning, and inflammation through large- scale, in-home survey methods, (3) advanced methods for longitudinal analysis, and (4) grant writing and professional development. In parallel with this training, this project has three research aims: (1) to determine how changes in exposure to proximal and distal social complexity collectively shape cognition and ADRD, (2) to determine how proximal and distal social complexity are associated with olfaction, in ways that may shape trajectories of cognition and ADRD, and (3) to determine how proximal and distal social complexity are associated with inflammation, in ways that may explain changes in cognition and ADRD. The training and research goals of this proposal will be overseen by a mentorship committee of accomplished experts in cognition and ADRD, sensory systems, chronic inflammation, and aging and the social context. This study will generate new insights on the collective impact of proximal and distal social factors on cognitive decline and ADRD. Further, this study will examine how social complexity shapes trajectories of olfaction and inflammation as mechanisms in the relationship between social complexity and cognitive health in a nationally-representative sample of older adults. These physiological frameworks of cognition and ADRD have yet to be contextualized in terms of social factors. This study will develop innovative measures of social network change, which are largely undertheorized, and that can be applied to future studies of cognitive aging and other health trajectories. The training and research activities of this award will equip Dr. Goldman with the skills to succeed as an independent investigator of the social context of sensory systems, disease processes, and their relationships with cognition and ADRD.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY/ABSTRACT This proposal seeks to investigate how social relationships (including social support, social integration, and negative interpersonal interactions) impact behavioral health treatment-seeking among post-Maria Puerto Rican migrants. Puerto Ricans are the second-largest Latinx group in the United States (US) and have the highest rates of behavioral health (BH) disorders among Latinx heritage groups. There is evidence that this may be due to the circular migration patterns that result from Puerto Ricans having US citizenship, which entails frequent disruptions to social networks. At the same time, Latinxs utilize BH services at lower rates than non-Latinxs, suggested a significant unmet treatment need. This study will investigate how the social relationships of post-Maria Puerto Rican migrants 1) influence perceived need for treatment and 2) influence service utilization. The results of the study can be used to inform culturally-congruent outreach efforts and BH services and suggest routes to reduce future BH treatment gaps with Latinx (im)migrant populations. The proposed study will have both quantitative and qualitative components. It will use prospective survey data from the parent study – the Adelante Boricua project – to determine salient social relationship influences on BH treatment outcomes. Qualitative interviews conducted for the proposed study will then explore in depth the associations between social relationships and BH treatment outcomes found in the quantitative aims. In addition to the proposed study, the training plan for this fellowship will provide a variety of opportunities to develop as a well-rounded, community-engaged health services researcher. These opportunities include advanced coursework to develop substantive and methodological knowledge, interdisciplinary team-based research experience, and mentored practice in working effectively with community advisory boards. The sponsor and co-sponsor both have extensive expertise with Latinx populations, including behavioral health (sponsor) and systems navigation (co-sponsor). They are supported by the institutional environment of the Boston College School of Social Work, which has a cadre of researchers who focus on Latinx and immigrant populations and a wealth of resources for conducted community-engaged research. The sponsorship team and institutional environment are ideal for completing the proposed study and training plan for this fellowship.

NIH Research Projects · FY 2025 · 2022-07

Summary Apicomplexan parasites have major impacts on human health e.g. Plasmodium falciparum causes malaria whereas Toxoplasma gondii and Babesia spp. cause opportunistic infections. Although this close-knit group shares their obligate intracellular life styles, they display a wide variety of asexual cell division modes. These differ between parasites as well as between different life stages within a single parasite species, but the start- and end-point is always a host cell invasion competent ‘zoite’. The number of zoites made per division round varies dramatically (from 2-90,000) and can unfold in several different ways by reshuffling the functional modules of 1) mother cytoskeleton disassembly, 2) DNA synthesis and chromosome segregation (D&S), 3) karyokinesis, and 4) zoite assembly (budding). Distinct cell division modes across Apicomplexa arise from variations in the order and sequence of the modules as well as the number of module repetitions. In the current model, cell division progresses in transcriptional waves mediated transcription factors that act on target genes that in turn bundle into the functional modules. However, little is known of the composition, regulators and wiring of the different modules, and how this leads to the diversity of cell division modes in Apicomplexa. The research team hypothesizes that these questions can be answered by a comparative systems biology approach, starting with parasites representing different diverse and ‘exotic’ division cell division modes wherein particular modules are amplified, or combined differently: Babesia divergens binary fission, P. falciparum schizogony, Sarcocystis neurona endopolygeny without karyokinesis, T. gondii asexual endodyogeny and T. gondii pre-sexual endopolygeny with karyokinesis in the definitive host. This approach takes advantage of the single cell sequencing revolution combined with computational network analysis approaches. Firstly, single cell transcriptomic and epigenomic maps of the five cell division modes will be generated and analyzed to define the effectors contained in each specific module. A subset of uncharacterized effectors in the poorly characterized karyokinesis and cytoskeleton disassembly modules will be experimentally validated by gene knock-downs. Secondly, chemical and genetic perturbations combined with single cell sequencing will enable the assembly of causal gene regulatory networks (GRNs) across all division modes. Candidate module controllers in these GRNs will be validated by reprogramming and/or genetic perturbation experiments: changing (parts of) the division mode in specific parasites. This work will answer elusive questions regarding apicomplexan specific biology within barely studied functional modules, as well as how apicomplexan cell division flexibility is wired. Thirdly, the proposed work will produce extensive community resources comprising single expression and chromatin accessibility atlases across five different cell division modes and parasite species. Moreover, data sets will be searchable across systems in real time for any biological feature of interest by web-based Apps that will be incorporated in VEuPathDB and enable querying the data for biological questions beyond cell division.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Violence and humanitarian crises are common in the lives of children around the world, particularly in low- and middle-income countries. Exposure to war-related violence is detrimental to the mental health of parents and children, but research exploring mechanisms by which emotional and behavioral disruptions are transmitted to subsequent generations remains nascent, especially in Sub-Saharan Africa. To help address this gap, a study of war-affected youth has been underway since 2002 following a cohort of war-affected children—many, both male and female, former child soldiers—in Sierra Leone into young adulthood, and now parenthood. A prior NICHD-funded R01 (R01HD073349) demonstrated how childhood war-related trauma and loss contributed to mental health problems in adulthood. In 2017, a cross-sectional sample of intimate partners and biological offspring was added to the sample to examine linkages between early trauma exposure and both intimate partner and parent-child relationships. Knowledge to date of how war-related stressors “get under the skin,” to become heritable biophysical traits and the implications for the mental health of the next generation remain limited. Of relevance are the Research Domain Criteria-related constructs of self-regulation and stress reactivity and how they influence emotional, cognitive and social functioning of children. The proposed research comprises a significant advance in the 20-year history of this study by advancing understanding of potential biological embedding of stress responses intergenerationally. Building on four prior waves of data collection, biological measures of stress reactivity and self-regulation (autonomic nervous system reactivity, inflammation, telomere length) will be collected in a sample of parents exposed to significant trauma in childhood and extended also to intimate partners and offspring. Strong capacity-building collaborations with Sierra Leone’s University of Makeni (UNIMAK) and Kenema Government Hospital (KGH) will support the ethical collection of new stress biomarker data and clinical assessments of parent-child synchrony, health, and anthropometric data in biological offspring aged 7–24. Key study innovations are (a) rare prospective data on parental trauma exposure and longitudinal information on risk and protective factors operating across the social ecology; (b) data on biological embedding of stress responses related to parental trauma; and (c) the opportunity to examine both mental health and physiological outcomes in biological offspring in war-affected families over time. Advanced statistical techniques (e.g., latent class growth models, structural equation models, lagged effects models) will articulate mechanistic pathways and priority targets for intervention. Collaborations between investigators, UNIMAK, KGH, as well as community advisory boards will inform study implementation, ensure strong retention of participants, and provide channels for dissemination. Analyses will inform screening tools to identify families for preventive interventions. Intervention targets identified have implications not just for war-affected settings, but also for assisting diverse populations affected by violence and trauma, including migrants and refugees.

NIH Research Projects · FY 2024 · 2021-09

Background: Gender minority youth (GMY; children, adolescents, and young adults whose gender differs from their birth-assigned sex) have a disproportionately high risk for serious mental health problems relative to cisgender youth (whose gender aligns with their birth-assigned sex). These mental health disparities are exacerbated by treatment engagement barriers, including the dearth of mental health providers trained in evidence-based practices (EBPs) that help GMY engage and benefit from mental health treatment. These EBPs are treatment tailoring techniques for any psychotherapy modality; they are not a standalone clinical intervention. Research: This research will develop and pilot test a training intervention to increase mental health providers’ use of EBP with GMY. Intervention design (Aim 1) employs community-engaged and user-centered design methods with key stakeholders: GMY, their parents, and mental health providers. The training will target three mechanisms hypothesized to result in behavioral change in providers (increased EBP adoption): knowledge, attitudes, and self-efficacy. mHealth technology and AI will enhance intervention scalability. Intervention refinement (Aim 2) will involve providers completing usability testing via individual meetings wherein they complete the training and provide real-time feedback on content and functionality. Feedback from usability testing will be used to iteratively refine the training and ensure its readiness for pilot testing. The pilot test (Aim 3) will be an open trial in a multi-clinic mental health agency, aimed at examining the feasibility and acceptability of conducting a future RCT. Effectiveness and implementation data from both providers and consumers (GMY and their parents) will be collected and analyzed. Candidate’s Career Development, Goals, and Environment: The proposed Mentored Patient-Oriented Research Career Development Award (K23) will provide Dr. Price with the advanced training and skills necessary to launch an independent research program focused on increasing EBP implementation to reduce documented mental health disparities. Formal training and mentorship in (T1) mechanism-driven intervention development and testing, (T2) user-centered design, (T3) community-engaged research, and (T4) implementation science will support the successful execution of this research and Dr. Price’s career development. The immense resources available at Boston College, coupled with the vast expertise of mentorship and advisory team members, will further ensure the success of the research

NIH Research Projects · FY 2024 · 2021-08

PROJECT ABSTRACT This research program aims to develop novel modeling methods, tools, and guidelines to incorporate racialized lived experiences into mathematical models of infectious disease transmission by explicitly modeling structural drivers of racial disparities in infectious disease exposure, susceptibility and severity, and consequences. In particular, this research will intentionally engage with geographic disparities in the United States through geographic information systems (GIS) coded data to highlight the importance of social context and determinants across the life course to the transmission of infectious diseases. We will employ systems science to analyze in silico simulations and post-hoc data analysis of simulation output to understand the structural drivers of infectious disease disparities. In silico simulation allows for the development of synthetic populations that represent individuals and households (and their characteristics) within a particular geographic area. We plan to modify the model structure to explore the impact and specificity gained by adding a variety of model characteristics, including stochasticity, natural history, and environmental influence. We then aim to perform comprehensive sensitivity analyses accounting for social and political context and the incorporation of multiple interacting factors that may help identify patterns in spread of particular disease types. Ultimately, the goal of the in silico simulations is to mathematically link policy effects to health outcomes through racialized lived experiences (represented and parameterized as agent characteristics). While the modeling frame will be flexible, we will use data on SARS-CoV-2 and influenza as two examples to demonstrate the feasibility of the methods we develop. The results from this work will allow us to develop policy recommendations for structural interventions to reduce racial disparities in infectious disease outcomes. Incorporating structural interventions into the model structure will require flexibility to account for the interference and feedback with individual behaviors. The structural interventions we plan to examine using in silico simulations include eliminating residential segregation, increasing accessibility to stable housing, reducing income inequality, and distribution of healthy food choices represented by real-world programs across the United States. This research will lay the groundwork to inform ongoing control of existing and emerging infectious disease pathogens and prevent the unequal health- and cost-related burdens on communities of color.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT Following decades of discriminatory policies and underinvestment in affordable housing, the 1.2 million households residing in our nation’s public housing (PH) developments often live in conditions of concentrated poverty, unhealthy and unstable housing and community contexts, and constrained social and economic opportunity. These social determinants of health drive substantial health disparities, with PH residents experiencing elevated levels of mortality and morbidity across numerous health domains. In response, current policy efforts seek to redevelop PH into mixed-income communities in order to deconcentrate poverty, create healthier housing environments, decrease community stressors, and enhance community resources. It is essential to delineate the repercussions of such policies on health disparities and to understand the mechanisms underlying effects. This project seeks to exploit a multi-arm natural experiment of PH redevelopment to evaluate whether improving housing quality, limiting external displacement, and creating mixed-income communities improve the physical, mental, and behavioral health of PH residents, including children, adults, and older adults. We will further assess the social, environmental, and physiological mechanisms underlying such effects. Finally, we will address whether effects vary across resident age, gender, and race/ethnicity. The study will employ a rigorous mixed-methods design to follow 1068 individuals from 600 households in a Boston PH community undergoing redevelopment. The redevelopment plan will move quasi-randomly selected subsets of residents into new high quality PH, or displace them offsite followed by a return into new high quality mixed-income housing. We will compare these residents to a matched control group who will remain in place. Our interdisciplinary team will collect four waves of in-person surveys, direct environmental assessments, and direct physiological stress measurements, as well as annual geocoded administrative data and intensive qualitative interviews with a subset of respondents. This innovative combination of sources will provide data on resident physical, mental and behavioral health; physiological stress; social connections and collective efficacy; housing quality and disorder; and neighborhood crime, pollution, social problems and resources. Intent-to-treat, difference-in-differences, and average treatment effect models will provide rigorous evidence of how housing quality, residential displacement, and residence in mixed-income housing affect resident health. Structural equation models and qualitative analyses will identify mechanisms underlying housing effects. Our results, unearthing causal and dynamic processes underlying health disparities, will provide innovative new data on social determinants of health to inform models of housing and community redevelopment in the context of concentrated poverty.

NIH Research Projects · FY 2025 · 2021-07

Abstract Despite effective anti-retroviral therapy (ART) that maintains HIV at non-detectable levels in plasma, HIV is not eradicated. When individuals are off ART, or during viral blips, CNS viral reservoirs can quickly rebound. We and others have found that a population of CNS perivascular macrophages (PVMs) function as a major target for HIV and SIV infection in the CNS, and the viral reservoir that persists with ART. Intracisternal (i.c.) injection of superparamagnetic iron oxide nanoparticles (SPIONs) demonstrate PVMs take up SPIONs within the CNS, accumulate with SIV infection, and traffic out of the CNS where they are found in cervical draining lymph nodes (cLNs), dorsal root ganglia, spleen, and bone marrow. Importantly, SPION-labeled CD163+ macrophages in the cLN can be productively infected with SIV as evidenced by SIV-p27 immunoreactivity. It is our overall hypothesis that an identifiable population of PVMs in the CNS functions as a cellular reservoir of rebound HIV and SIV during ART, and after ART cessation, and these cells can leave the CNS with virus that potentially reseeds the periphery. To test our hypothesis, we propose to use a CNS-penetrant colony-stimulating factor 1 receptor (CSF1R) inhibitor (BLZ945) that ablates these reservoir-reseeding CNS PVM early (3 months after ART initiation) and late (5 months after ART initiation) during ART in virally suppressed macaques, and in animals undergoing ART cessation. We propose to use 2 different fluorescently tagged SPIONs, injected intra-CSF just prior to early and late BLZ945 treatments, in order to define the role of resident and repopulated PVMs to function as a viral reservoir of SIV, and block their ability emigrate with virus. We propose to test our hypothesis with two Specific Aims: Aim 1 will determine the extent to which CSF1R blockade can eradicate SIV in the brain and block lymphatic-dependent reseeding of virus from the CNS to the periphery in the presence of ART; and Aim 2 will determine whether CSF1R blockade can prevent reactivation of SIV reservoirs in the brain and repopulation of viral reservoirs from the CNS to the periphery after ART interruption.

NIH Research Projects · FY 2025 · 2020-05

Project Abstract Post-translational modifications (PTMs) dramatically expand the chemical and functional space accessible to proteins. Over the last 25 years, the landscape of known PTMs within the mammalian proteome has expanded at a dizzying speed, driven by the remarkable advances in mass-spectrometry based proteomics. However, functional consequences of most of these PTMs remain poorly characterized. At the core of this deep knowledge-gap – on a critically important facet of our biology – lies the difficulty of homogeneously generating eukaryotic proteins carrying a desired PTM at chosen site(s) to study how the presence of the modification alters the protein’s properties in vitro and in cellulo. For most PTMs, the precise biochemical origin is either poorly understood or challenging to reconstitute without additional pleiotropic consequences. The noncanonical amino acid (ncAA) mutagenesis technology, enabled by genetic code expansion (GCE), provides an exciting solution for this problem by enabling site-specific incorporation of a modified residue into virtually any site of any protein expressed in living cells. However, application of this technology in mammalian cells has faced significant technical limitations, including restricted structural diversity of ncAAs, inefficient incorporation, and difficulties in extending it to hard-to-transfect cells. Over the last five years, we have systematically addressed these challenges by: A) Establishing new platforms to incorporate new structural classes of ncAAs, B) Developing a mammalian cell-based directed evolution platform to engineer the ncAA-incorporation machinery, C) Creating optimized expression systems and delivery vectors for efficient ncAA incorporation in diverse mammalian cells and tissues. These advances have already enabled us to model several new PTMs in mammalian cells, including tyrosine sulfation and phosphorylation, arginine citrullination, dual acetylation/methylation of lysine, serotonylation of glutamine, etc. In the next five years, we will continue our quest to expand the scope of this technology for modeling an even larger subset of important PTMs associated with the mammalian proteome. Additionally, using our novel mammalian cell- based directed evolution platform, we’ll systematically optimize the ncAA incorporation machinery to improve its scope and robustness. Finally, using our powerful new ability to site-specifically introduce previously inaccessible PTMs into proteins expressed in mammalian cells, we will develop novel approaches to study several different facets of their biology: 1) Characterize the unique interactome of a PTM-labeled protein (using proximity labeling/MS-proteomics). 2) How PTMs alter the conformational dynamics of complex mammalian proteins (using single-molecule FRET). 3) How certain PTMs enhance the immunogenicity of human proteins (using novel display strategies). In addition, the research proposed here will fundamentally advance the scope of the GCE technology for application in higher eukaryotes for numerous additional applications, which will have broad and deep impact beyond the scope of this proposal.

NIH Research Projects · FY 2025 · 2020-02

Summary Toxoplasma gondii is an obligate intracellular apicomplexan parasite causing severe opportunistic infections. Current drugs are prone to induce hypersensitivity, especially upon long-term use. Under this proposal the unique cell division process will be interrogated to identify putative new drug targets. Toxoplasma divides by a distinct internal budding process whereby two daughter parasites are assembled within a mother cell. The cortical membrane skeleton composed of flattened alveolar vesicles supported by an epiplastin protein network and 22 subpellicular microtubules (MTs) is nucleated on the centrosomes and assembles in an apical to basal direction. In the second half of division the posterior end of the daughter buds (i.e. the basal complex or BC) starts to taper driven by Myosin J (MyoJ). Absence of MyoJ only modestly impact parasite viability, even while it leaves the BC somewhat unconstricted, fitting classic data on cell division resistance to actin depolymerizing agents. However, preventing assembly of the BC altogether by depleting or overexpressing the BC scaffolding protein MORN1 results in parasites with fraying MTs unable to complete cell division and has dramatic impact on viability. To unravel this intriguing process, under an R21 grant the BC was proteomically dissected through proximity dependent biotinylation (BioID) on 8 BC components. This revealed 4-5 different protein complexes aligning with the ultrastructure. Two key observations are further pursued under this proposal: 1. A putative MT Associated Protein, MAP1B-L1, appears to assemble on the (+)-ends of the subpellicular MTs and is essential for BC assembly and parasite viability; 2. Several kinases and phosphatases identified indicate the BC is regulated by differential phosphorylation. Under Aim 1 MAP1B-L1 and another critical BC MAP dubbed MAP1B- L2 will be tested for MT binding capacity by generating deletion mutants in the parasite, in vitro using the identified MT binding domains, and by exogenous expression in the Xenopus leavis axon guidance model as relevant to related MAPs. Under Aim 2 we will pursue four additional candidates identified in the BioID approach with a likely essential function, which are all hypothetical proteins narrowly conserved in internally budding parasites and harbor putative adhesion domains. In addition, we will apply fast acting TurboID on BC components transiently associating with the assembling BC like MAP1B-L1 as these were likely undersampled in the current dataset, yet define the essential step of the BC in cell division. Under Aim 3 we will subject 2 kinases and 1 phosphatase to synthetic lethality screening using the genome wide CRISRP/Cas9 library. Preliminary data of the first kinase tested already demonstrates experimental feasibility and revealed interesting new insights. Combining the proteomic and genetic data sets is expected to provide a solid basis to assemble the wiring diagram of the BC. In the current working model the BC is first assembled on the MT (+)-ends, followed by recruitment of adhesion proteins to keep the MT-ends together. Overall, this is expected to deliver exciting new insights into internal budding, how it differs from schizogony, and could highlight new drug targets.

NIH Research Projects · FY 2025 · 2019-01

Project Summary A major thrust of the proposed studies is founded on the principle that a molecule's contour is key to its ability to elicit biological response, making it crucial that methods for precise alteration of its three-dimensional shape are available. The PI's long-standing experience in the design and development of olefin metathesis strategies, catalysts and methods will serve toward establishing innovative ways of transforming highly complex but readily available (i.e., purchasable and inexpensive) bioactive natural products to their corresponding skeletally altered analogs. The resulting entities, as shown recently in the PI's NIH-funded program, will represent new drug leads for the same or a different disease area. Molecules containing a medium or large ring and at least one olefin will be at the center of the proposed investigations. A new class of catalysts will be designed to promote efficient ring-opening metathesis of otherwise unreactive rings; after chain extension by cross-metathesis or olefin isomerization, ring-closing metathesis will be used to access expanded or contracted cyclic structures, respectively. Another aspect of the proposed studies will entail developing ways of precisely altering the shape of complex and easily accessible cyclic or polycyclic compounds that do not contain a readily modifiable functional group. New strategies will thus be developed for introducing unsaturation and then using olefin metathesis-based processes to expand or contract their ring(s), resulting in precise alteration of the molecule's overall shape. Another key aim will be the development of catalytic multicomponent diastereo-, and enantioselective transformations that will transform readily accessible molecules to highly complex and readily modifiable products, which can be used as platforms for the generation of a variety of bioactive compounds and potential drug leads.

NIH Research Projects · FY 2025 · 2018-09

Project Summary A cardinal feature of anxiety disorders is exaggerated fear to cues signaling threat. The prevailing view of the neural circuit for fear learning is a division of labor in which the amygdala and associated forebrain regions signal threat probability, and brainstem regions organize fear output. This view is the intellectual foundation for proposals that forebrain threat dysfunction drives exaggerated fear in anxiety disorders. Much more than organizing fear output, my laboratory is showing brainstem networks compute prediction error – a learning signal to drive fear learning. Further, brainstem networks signal threat – a function purported to be specific to the forebrain. This proposal will reveal brainstem networks that signal threat probability, compute prediction error, and organize fear output. Aim 1 will detail the emergence of brainstem threat and behavior signaling dynamics. Female and male rats will receive Neuropixels implant through a complete dorsal-ventral brainstem axis. Thousands of single units will be recorded from 20+ brainstem regions during a fear discrimination procedure that produces selective learning to a threat cue. Firing analyses during the cue period will reveal the emergence of brainstem network threat signaling and tracking of diverse behaviors over fear learning. Aim 2 will establish a framework for brainstem prediction error dynamics. Firing analyses during the outcome period will link brainstem network firing dynamics for prediction error that precede the emergence of fear learning. Aim 3 will reveal forebrain inputs shaping brainstem firing dynamics and fear learning. Rats will receive brainstem Neuropixels implant. AAV2-retro in a brainstem region and cre-casp3 in a forebrain region will be used to delete specific inputs to the brainstem (e.g. prelimibic cortex neurons projecting to the periaqueductal gray). Firing analyses comparing casp3 and control rats will reveal the dependence of brainstem firing dynamics (threat, behavior, and prediction error) on forebrain inputs. Aim 4 will chemogenetically manipulate brainstem firing to diminish prediction error computation and fear learning. Rats will receive brainstem Neuropixels implant. Half will then receive excitatory DREADD infusions in regions flanking the periaqueductal gray – sources of a tonic prediction error organized by firing inhibition. Actuator injections (JH60), but not saline injection, will excite brainstem firing – blocking the tonic prediction error network. Firing analyses will reveal the effects of network interruption on brainstem firing dynamics for threat, behavior, and prediction error. This proposal will extend scientific knowledge by uncovering core threat functions of brainstem networks. The proposal will further reveal how forebrain inputs shape brainstem firing dynamics that signal threat, compute prediction error and organize specific fear behaviors. This knowledge is essential to developing effective anxiety disorder treatments aimed to reduce fear.

NIH Research Projects · FY 2026 · 2018-05

Project Summary. New functional group transformations can enable synthetic chemists to disconnect molecules in new ways, thereby enabling new synthesis strategies. Ideally such new technologies enable the synthesis of important molecules from untapped, perhaps more readily available, starting materials. The proposed research will extend our fruitful studies on catalytic diboration, catalytic cross-coupling, and catalytic boronate rearrangements to address important new stereoselective transformations. Our strategies are keenly focused on developing processes that are readily accessible to the end-user without specialized techniques, equipment, or materials.

NIH Research Projects · FY 2026 · 2017-09

Project Summary Polyploidy frequently arises in response to injury, aging, and disease. Despite its prevalence, major gaps exist in our understanding of how polyploid cells alter cell, tissue, and organ physiology. This is part because polyploid cells are heterogeneous and arise in distinct ploidy states (mononucleated and multinucleated) with each nucleus having varying sets of chromosomes. It is therefore hypothesized that the heterogeneity of ploidy states provides cells with a vast repertoire of mechanisms for tissue growth, repair, and adaption to stress. Using the fruit fly, Drosophila melanogaster, as a model my laboratory has identified the core cellular and genetic mechanisms regulating polyploid cell growth in epithelial wound repair and aging as well as novel physiological roles for polyploidy in resistance to genotoxic stress and enhancing tissue mechanics. Since mononucleated and multinucleated cells arise in adult Drosophila epithelium in response to injury, similar to vertebrates, we can determine how a cell’s ploidy state affects its cellular, tissue, and organ physiology and disease susceptibility. The goals of this project are to 1) determine how ploidy state, both mononucleated and multinucleated epithelial cells responds to and protect against UV-induced DNA damage and 2) elucidate how ploidy state alters a cell’s actomyosin network to enhance epithelial tension and restore organ movement in the fruit fly post wound repair. Doing so, will provide fundamental insights into the versatility of polyploidy and how a cell’s ploidy state impacts human health and disease.

NIH Research Projects · FY 2024 · 2015-09

PROJECT SUMMARY/ABSTRACT Catalytic Processes for Stereoselective Radical Cyclization Reactions Cyclic structures, including both carbocycles and heterocycles, are common motifs of natural products and synthetic compounds with important biomedical activities. Among different approaches for preparing cyclic molecules, radical cyclization represents one of the most powerful approaches for construction of ring structures. Among a number of inherent synthetic advantages, radical reactions typically proceed at fast reaction rates under mild and neutral conditions in a broad spectrum of solvents and exhibit significantly high functional group tolerance. Furthermore, radical processes have the capability to perform in a cascade fashion, allowing for the rapid construction of complex molecular structures with generation of multiple stereogenic centers. To further enhance the synthetic applications of radical cyclization, new approaches will be needed for achieving high control of their reactivity as well as stereoselectivity, especially enantioselectivity, challenging issues that are intrinsically associated with the “free” nature of radical chemistry. Guided by the mechanistic principles of metalloradical catalysis (MRC), this proposed research explores a fundamentally different approach for controlling stereoselectivity of both C- and N-centered radical reactions. Cobalt(II) porphyrins [Co(Por)], as stable 15e metalloradicals, can enable the activation of diazo compounds and organic azides to cleanly generate C- and N-centered radicals, respectively, with N2 as the only byproduct in a controlled and catalytic manner. The initially-formed C- and N-centered radicals, which are termed as a-Co(III)-alkyl radicals and a-Co(III)-aminyl radicals, respectively, remain covalently bonded with [Co(Por)]. They can undergo common radical reactions, such as radical addition to alkenes and hydrogen-atom abstraction, but with effective control of reactivity and stereoselectivity by the porphyrin ligand environment. In addition to the radical nature of [Co(Por)], the low dissociation energy of Co–C and Co–N bonds plays a key role for the successful turnover of the Co(II)-based catalytic processes, resulting in effective radical cyclization reactions. Through the support of D2-symmetric chiral amidoporphyrin ligands with tunable electronic, steric, and chiral environments, Co(II)-based metalloradical catalysis (Co(II)-MRC) will be applied for the development of various radical cyclization processes for stereoselective construction of both carbocylic and N-heterocyclic compounds with different ring sizes and varied degrees of molecular complexity. We hope these studies will ultimately lead to the development of cost-effective and environmentally benign radical cyclization processes that can be successfully applied for the stereoselective synthesis of biologically important natural products and pharmaceutically interesting small molecules.