Grants

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Allergic diseases persist throughout a person’s lifetime, and the mechanisms underlying maintenance of the Th2 cells that drive these diseases are poorly understood. Chronic inflammation canonically drives T cell exhaustion in chronic infection and cancer, while Th2 cells conversely persist despite chronic inflammation We recently created a single-cell transcriptomic atlas from human tissues with allergic type 2 inflammation. A conserved set of Th2 cells was identified across tissues, including an aberrant memory-like population co-expressing TCF1 and LEF1, with evidence of chronic activation. This transcriptional profile mirrors the progenitor/stem-like CD8+ T cells that have been described in cancer and chronic infection, and we hypothesized that this Th2 cell population may serve as the reservoir that perpetuates Th2 responses. We named this cell the Th2 cell multipotent progenitor (Th2-MPP). Ex vivo functional studies established that these cells couple self-renewal with terminal differentiation in Th2, TFH- like, and Treg cells. We propose that aberrant cell-cell interactions and alarmin signaling networks in allergic tissues orchestrate an epigenetic state in Th2-MPP that enables self- renewal in the face of chronic antigen burden. The specific aims of this research strategy will investigate the epigenetic mechanisms and cell- cell interactions driving human Th2-MPP maintenance (Aim 1). Moreover, we will functionally interrogate candidate pathways through the development and characterization of a mouse model of chronic type 2 pulmonary inflammation, with temporal conditional genetic ablation of putative regulators of Th2 maintenance (Aim 2). These complimentary human and mouse immunology approaches will yield fundamental insights into the chromatin states of type 2 lymphocytes in barrier tissues and signaling mechanisms that drive this profile. Concurrently, the mechanistic studies of candidate pathways in mice will establish new avenues for the development of therapeutic modalities. This study combines mechanistic mouse models and primary human tissue analyses with cutting-edge single cell bioinformatics to provide the candidate new training in key elements of translational immunology. Through support from the co-mentors and Advisory Committee, the candidate will be well-positioned to transition to independence as an investigator, with the goal of identifying new therapeutic targets for the treatment of chronic inflammatory diseases.

NIDCR - National Institute of Dental and Craniofacial Research

PROJECT SUMMARY The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, respiration, and speech. The TMJ is comprised of a network of muscles, ligaments, and a fibrocartilaginous disc and condyle. TMJ osteoarthritis (OA) causes cartilage loss and pain. TMJ OA poses a major clinical problem, but there are no regenerative therapies. Understanding stem/progenitor cells is critical knowledge in organ tissue regeneration. We previously defined TMJ Lgr5-expressing cells as secretory niche cells critical for supporting TMJ cartilage progenitor cells in a canonical Wnt inhibitory niche. We also defined two secreted Wnt inhibitors, SOST and DKK3, as critical parts of the TMJ cartilage progenitor cell niche. We showed that therapeutic intra- articular injections of SOST ameliorate TMJ OA in a preclinical, mini-pig post-traumatic TMJ OA animal model. However, the identity of the TMJ cartilage progenitor cells regulated by Lgr5+ secretory niche cells and therapeutically targeted by cWnt inhibition is unknown. This R01 renewal proposal builds logically on our previously funded R01. We will investigate candidate TMJ cartilage progenitor cells and their regulatory niche critical for TMJ development, homeostasis, and regeneration. This proposal will: 1) establish the TMJ condyle as a sophisticated model for studying cartilage progenitor cells; 2) leverage basic science to design TMJ OA drugs. These foundational studies are critical for the advent of novel minimally invasive TMJ regenerative therapies.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Allogeneic hematopoietic stem cell transplant (HCT) recipients are at high risk of severe morbidity and mortality due to respiratory viral illnesses, including COVID-19. Despite two mRNA SARS-CoV-2 vaccines that are highly effective for the general population, HCT recipients have reduced immune responses to vaccines and remain at risk. This population’s ongoing risk is amplified by the emergence and circulation of SARS-CoV- 2 variant strains, relaxation of mask mandates and other public health measures, and waning effectiveness of SARS-CoV-2 monoclonal antibodies. New vaccination strategies are urgently needed for patients with hematologic malignancies, both to protect these patients and to reduce viral reservoirs that otherwise would allow for generation of new variants. To inform these strategies, we will evaluate the unique role of adoptive transfer of humoral and cellular immunity in HCT recipients, which will simultaneously use vaccine response as a mechanism to evaluate immune reconstitution. These studies will test our overarching hypothesis that these patients have distinct and altered immune responses to mRNA SARS-CoV-2 vaccination, resulting from their underlying disease, past immunomodulatory therapies, and the unique donor-to-recipient immune dynamics. The Specific Aims of this proposal are: Aim 1: Characterize the relationship between donor and recipient SARS-CoV-2 immunity in matched-related donor allogeneic HCT patients through analysis of humoral responses and transfer of immunity post-transplant from banked samples; Aim 2: Describe the correlation between donors’ pre-harvest cellular responses and recipients’ post-transplant humoral SARS-CoV-2 vaccine responses through creation of a prospective study of HCT recipients and their matched-related donors; and Aim 3: Evaluate donor v. recipient Ag-specific T and B cells and SARS-CoV-2 clonal breadth and depth after re-vaccination post-transplant to assess immune reconstitution, using T and B cell receptor repertoire analyses methods. We expect that completion of these aims and the associated training objectives will generate clinically applicable preliminary data to inform vaccine development and policy for patients with hematologic malignancies. My long-term career goal is to become an independently funded clinician-scientist and leader in translational vaccinology with a focus on developing precision vaccines for immunocompromised adults. I will achieve this through: 1) investigation of immunologic pathways that promote or inhibit vaccine-induced responses for patients with hematological malignancies, and 2) translation of these findings into novel vaccines via early-phase clinical trials. Brigham and Women’s Hospital and the Precision Vaccines Program at Boston Children’s Hospital are highly collaborative research environments within the broader Harvard Medical School community that will provide abundant resources and institutional support to complete the described aims.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Pathogenic bacteria have developed an array of strategies to undermine the host's defense mechanisms. In the context of non-Typhoidal Salmonella Typhimurium, a notable strategy involves the confinement of a single bacterium within a host vacuole called the Salmonella Containing Vacuole (SCV). This approach potentially provides an evolutionary advantage: by ensuring one bacterium per SCV, the host must target each SCV individually to eliminate the bacterial load, as opposed to confronting a vacuole harboring multiple bacteria clustered together. This mechanism could potentially extend the time required to combat the infection. Moreover, a single bacterium residing within an SCV exploits all accessible nutrients for replication and division. Conversely, multiple bacteria clustered within a single vacuole may engage in nutrient competition. Hence, understanding the fundamental mechanism of bacterial division in conjunction with vacuolar scission is imperative for gaining deeper insights into the pathogenic strategies employed by Salmonella enterica. Prior to this proposal we engineered a series of genetically minimal pathogenic strains that eliminates redundancy within the complex SPI-2 effector gene repertoire of Salmonella enterica serovar Typhimurium. Using this unique resource, here we will determine how a small network of SPI-2 T3SS effector proteins coordinate the complex events involved in SCV membrane scission and bacterial division within the host cell. This includes determining the location and host substrates of effector proteins at the SCV membrane using single cell particle tracking and live cell imaging (Aim 1). We will also investigate the molecular mechanisms of individual effector proteins that target a novel Rab-family GTPase defense system of the host (Aim 2). The resulting cellular and biochemical theories will be tested in murine models of systemic disease that are designed to evaluate effector protein functions at single cell resolution (Aim 3). Developing new drugs that target bacterial effector – host enzyme complexes would be an innovative approach to combat emerging infectious disease. While this idea holds great potential, the paucity of mechanistic information gleaned from deep studies into virulence factor functions has so far hampered their development as suitable drug targets. As a means to this end, the work performed here will allow us to predict new mechanisms of action for understudied Salmonella effector proteins and provide a glimpse into the structural-based evolutionary progression of a related pathogen groups.

NSF

Complex manifolds are higher-dimensional geometric spaces defined using the complex numbers. This project focuses on two special kinds of such spaces, namely Calabi-Yau manifolds, and Kähler-Ricci solitons. These types of complex manifolds have a wide array of applications throughout physics and mathematics, and for this reason have attracted a great deal of attention in recent years. This project will focus on constructions and classifications of such complex manifolds. The results will deepen our understanding of the geometry of complex manifolds as a whole and more broadly will further advance our knowledge through connections to other subjects ranging from algebraic geometry, topology, and analysis to physics. The project will also be used to help support researchers interested in contributing to these active and competitive fields. More technically, the project aims to further our understanding of the singularity development both of the Kähler-Ricci flow and of collapsing Calabi-Yau manifolds. Characterizing the development of singularities along the Kähler-Ricci flow is one of the fundamental questions in geometric analysis and is expected to reveal deep ties between geometric analysis, algebraic geometry, and topology. On the other hand, the analogous collapsing Calabi-Yau picture has many applications, including to physics. These two programs fit into a common framework, each with a given singularity model (respectively Kähler-Ricci solitons and complete non-compact Calabi-Yau metrics) and a corresponding type of degeneration (respectively the Kähler-Ricci flow and families of collapsing Calabi-Yau manifolds). The project will (1) construct examples of non-compact singularity model geometries, (2) describe the moduli of these spaces and (3) analyze the corresponding degenerations. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Delaware Aviation Museum Foundation

Delaware Aviation Museum Foundation is an active grantmaking foundation based in Mardela Spgs, MD. Focus: arts. Contact the foundation directly for current funding opportunities.

Delaware Community Foundation

Delaware Community Foundation is an active grantmaking foundation based in Wilmington, DE. Focus: philanthropy. Contact the foundation directly for current funding opportunities.

Delaware

Delaware County

Delaware

Economic Development

Delaware

Delaware County

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Delaware County

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Delaware County

Regional Council Capital Fund - RC4

Delaware County Broadband Initiative

EDF

Delaware County IDA/Amphenol Capital

Delaware

Delaware County Lifeguard Enhancement program

Walgreen's 9687

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Walgreen's 11010

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Walgreen's 11034

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Walgreen's 11045

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Walgreen's 11047

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Walgreen's 11048

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Walgreen's 11049

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Walgreen's 11051

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Walgreen's 11055

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