Geisel School of Medicine Announces 2021 Munck-Pfefferkorn Grant Awards

Named in honor of Geisel School of Medicine late emeritus professors Elmer Pfefferkorn, PhD and Allan Munck, PhD—outstanding scientists, teachers, and mentors who inspired generations of researchers and physicians—the Elmer R. Pfefferkorn & Allan U. Munck Education and Research Fund Novel and Interactive Grant Initiative provides seed funding for research projects that have high potential to lead future sponsored projects or programs that encourage collaborations among and across Geisel faculty.

Since 2016, the Munck-Pfefferkorn Grant Awards have supported faculty investigators launching new and innovative yearlong projects. This year Munck-Pfefferkorn Grants have provided more than $420,000 in seed funding to Geisel researchers. Additionally, more than $100,000 in matching departmental funding will be provided to this year’s recipients.

Congratulations to this year’s Munck-Pfefferkorn Grant recipients and their projects:

Detecting COVID-19 Central Nervous System Dysfunction Using Central Auditory Tests

Jay C. Buckey, MD (Medicine/Biomedical Research), Robert Roth, PhD (DHMC Department of Psychiatry), Richard Zuckerman, MD, MPH (Infectious Disease), Jonathan Lichtenstein, PsyD, MBA (DHMC Department of Psychiatry), Christopher Niemczak, AuD, PhD (Medicine/Biomedical Research), Erika Skoe, PhD (UConn, Speech, Language, and Hearing Science)

This study aims to determine whether adults with cognitive fatigue (brain fog) after a COVID-19 infection have difficulty with the brain’s ability to process sound (i.e., understanding speech amid background noise.)

People with Post-Acute COVID syndrome (PACS), will be evaluated with central auditory tests (CATs) that measure how the brain processes sounds. If individuals with PACs have unusual difficulties with central auditory tasks, the tests could provide insight into brain dysfunction in those with post-acute COVID syndrome.

Objective, reliable tests are needed to diagnose individuals with PACS and cognitive fatigue. Understanding the central nervous system (CNS) consequences of COVID-19 and deploying objective, reproducible measures of CNS dysfunction is an urgent need. By using tests of the brain’s ability to process sound, this study seeks to show if CATs could reveal CNS dysfunction in those with persistent cognitive fatigue following COVID-19. This could change how this complication is detected and followed.

Because CATs can detect subtle CNS changes, the findings may also provide further evidence that long-term consequences of COVID-19 extend beyond the respiratory system and may affect more people than previously recognized. This study may also lead to objective identification of CNS dysfunction and potentially better therapeutic interventions for COVID-19 patients with persistent cognitive fatigue. If proven effective, this approach could help diagnose an important and disabling consequence of COVID-19 infection.

Applying Innovative Techniques to Detect Evolution in the Composition of Microbial Communities During Standard Treatment Protocols for Infection After Traumatic Injury

I. Leah Gitajn, MD, MS (Department of Orthopaedic Surgery at D-H), Benjamin Ross, PhD (Department of Microbiology and Immunology), Carey Nadell, PhD (Department of Biology)

Infection following trauma is one of the most prevalent and challenging complications faced by orthopedic surgeons in both military and civilian populations—with a treatment failure rate of approximately 30 percent, this suggests that current treatment strategies are clearly not adequate. The long-term goal of this research is to develop and optimize treatment strategies to more effectively detect clinically important microbes or microbial ecological relationships, and more effectively eradicate clinically relevant pathogenic communities in hardware associated infections using two highly innovative research methods: metagenomic sequencing and single cell three-dimensional biofilm imaging.

The objective is to examine evolution and/or change in microbial composition and ecology over the course of standard treatment for fracture related infection.

Overcoming Solid Tumor Immunosuppression with Engineered Armored NK Cells

Yina Huang, PhD (Departments of Microbiology and Immunology and of Pathology) and Charles Sentman, PhD (Department of Microbiology and Immunology)

CD8 T cells and natural killer (NK) cells are the major immune cell types responsible for antitumor immunity. Normally, each T cell has a unique antigen specificity that is conferred by its T cell receptor (TCR). For example, T cells that recognize an influenza-derived antigen would not react to a tumor antigen. Thus, the number of T cells capable of responding to any one antigen is very low, posing a problem for oncologists who wish to boost antitumor T cells. Over the past decade, immunologists have engineered tumor-specific chimeric antigen receptors (CARs) that can be introduced using viral vectors to confer tumor reactivity to all isolated T cells.

Administering CAR T cells specific for the CD19 can effect cures in more than 60 percent of pediatric and adult cancer patients with relapsed or refractory lymphoma, leukemia, or myeloma, dramatically improving outcomes for patients with liquid tumors, but CAR T cells show no efficacy for the treatment of solid tumors. Huang and Sentman recently engineered armored CAR T cells that exhibit excellent efficacy against several solid tumors; however, generating CAR T cells for clinical use is highly laborious because it requires engineering of the patient’s own T cells. Alternatively, allogeneic NK cells can be collected from the general blood donor population and continuously manufactured for off-the-shelf administration. Successful application of their armored platform to NK cells would allow them to break the immunosuppressive microenvironment in solid tumors to greatly benefit patient treatment, breaking the immunosuppressive microenvironment in solid tumors.

Single Cell and Spatial Omic Analyses of Lung Fibrosis and its Inhibition by Immunotherapy

Patricia Pioli, PhD (Department of Microbiology and Immunology) and Michael Whitfield, PhD (Departments of Biomedical Data Science and of Molecular and Systems Biology)

Systemic sclerosis (SSc) is a chronic autoimmune disease that results in widespread

fibrosis of the skin and internal organs, vasculopathy, and autoantibody formation. Despite modest advances in disease management for the treatment of SSc-associated interstitial lung disease, SSc continues to exhibit high mortality rates, primarily due to cardio-pulmonary involvement, with 30–40 percent of patients dying within 10 years of diagnosis.

Data from Pioli and Whitfield’s previous research implicate an immune-fibrotic axis, consisting of activated macrophages (MØs) and fibroblasts, as a primary driver of fibrosis in SSc. The premise of this proposal is that pro-fibrotic MØs induce fibroblast activation in SSc across multiple end-target organs. Therefore, targeted elimination of these MØs may provide an effective approach to treat SSc, as it is predicted to decrease fibrosis. Working collaboratively with Celdara Medical, they have designed a novel therapeutic approach to eliminate pro-fibrotic MØs using chimeric antigen receptor (CAR) T cells.

The goal of this project is to assess the utility of a novel cellular immunotherapeutic

to combat pulmonary fibrosis. Using cutting-edge genomics, they will identify MØ and fibroblast subsets in fibrotic and healthy lung pre- and post-CAR T cell treatment and will evaluate the potential clinical efficacy of MØ-targeting CAR T cell therapy by measuring collagen deposition, markers of inflammation, and tissue thickness in lungs. The studies will also generate biomarkers that will assist in assessing patient response to therapy. This translational research will form the foundation for clinical trials in patients, may identify novel targets for therapeutic intervention, and inform current treatment regimens for a patient population for whom few therapeutic options exist.

Identifying Novel Targetable Pathways in Dermatomyositis Skin Disease

Sladjana Skopelja-Gardner, PhD (Department of Medicine), Patricia Pioli, PhD (Department of Microbiology and Immunology), Michael Whitfield, PhD (Department of Microbiology and Immunology, of Molecular and Systems Biology, and of Biomedical Data Science), Dorothea Barton, MD (Department of Dermatology)

With an incidence of 10 cases per million people and lack of any animal or ex vivo disease models, dermatomyositis (DM) remains a debilitating disease without a cure or the understanding of the pathogenic mechanisms. ​DM patients present with inflammatory skin disease and most exhibit sensitivity to the ultraviolet (UV) sunlight rays, a prominent disease feature without a therapeutic solution.

The researchers’ long-term goal is to identify targetable pathways of DM skin disease and prevent photosensitive reactions in these patients. The objectives of the proposal are to elucidate how inherently dysregulated skin structural cells (keratinocytes) shape macrophage function in DM skin and to define the inflammatory responses to UV light in disease-relevant three-dimensional tissue models. Their central hypothesis is that the hyperinflammatory nature of DM keratinocytes propagates macrophage-mediated skin injury exacerbated by exposure to UV light. These studies will, for the first time, define how DM skin responses to UV light differ from healthy skin responses.

New Approaches to Define Global Impacts of Key Genes on Immune Cell Development and Differentiation

Edward J. Usherwood, PhD (Department of Microbiology and Immunology) and H. Robert Frost, PhD (Department of Biomedical Data Science)

Zbtb20, important in cellular differentiation and metabolism, is a member of the broad complex, tramtrack, bric-à-brac and zinc finger (BTB-ZF) family, which contains transcription factors that are critical for the development and correct functioning of the immune response.

This project will use single cell profiling techniques and novel statistical methods to determine the impact of the transcription factor Zbtb20 across the breadth of the immune system. Zbtb20 deficiency improved the ability of CD8 T cells to protect against tumors, suggesting Zbtb20 suppression as an attractive immunotherapeutic approach for cancer immunotherapy. Given its role in metabolic regulation, in addition to functions in developmental processes, it is likely Zbtb20 will play a role in development and/or differentiation in immune cells where it is expressed, such as macrophages, dendritic cell subsets, CD4 T cells and B cells.

Usherwood and Frost seek to determine the impact of Zbtb20 deficiency on immune cell development and differentiation both in response to tumors and infectious disease.

Together, this will provide key preliminary data necessary for a multi-PI R01 application focusing on identifying the global effect of genes such as Zbtb20 on the immune system and will provide compelling new analytical methods applicable to studying deficiency in any candidate gene across the full spectrum of immune cell types.

Zbtb20 has also been implicated in several cancer types, so an understanding of impacted pathways will help to dissect if it plays a role in oncogenesis.