This Project Grant award from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 Allergy and Infectious Diseases Research) provides $190,058 to the University of Massachusetts Medical School to investigate the role of the ADAM9 protein in the immune response to SARS-CoV-2 infection. The goal is to define how ADAM9 impacts the immunopathogenesis of severe COVID-19 and its effects on acute lung injury. The research will build on the grantee's preliminary findings...
This $131,988 Project Grant from the National Heart, Lung and Blood Institute, part of the Department of Health and Human Services, supports research targeting determinants of SARS-CoV-2 host interaction in airways. Funded through the Cardiovascular Diseases Research program, the grant aims to identify master regulator proteins that mechanistically regulate SARS-CoV-2 interactions in the airways. Using organotypic airway epithelial culture and systems biology tools at Columbia University, the...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 - Allergy and Infectious Diseases Research) provides $380,320 to the Trustees of the University of Pennsylvania, doing business as the Clinical Practices of the University of Pennsylvania, to conduct research on elucidating the lineage dynamics of optimal human CD8 T cell responses to SARS-CoV-2 and how CD8 T cell homeostasis is altered in Long COVID. The research aims to define human memory...
This federal Project Grant award of $705,557 from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) supports research to better understand the coordination of innate and cellular mucosal immunity in SARS-CoV-2 clearance. The primary objectives are to determine the contribution of monocytes in promoting T cell responses and viral control within the respiratory tract, and to define the effector mechanisms of...
This federal Project Grant award from the National Heart Lung and Blood Institute (CFDA 93.837 - Cardiovascular Diseases Research) provides $1,340,904 to researchers at the University of Virginia and University of Manchester to study the role of interleukin-13 (IL-13) and hyaluronan in the pathology of COVID-19. The key objectives are to: 1) Determine how IL-13 is induced and impacts hyaluronan matrix formation and lung inflammation in a mouse model of SARS-CoV-2 infection, 2) Investigate the...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), will provide $486,109 to the Mayo Clinic Arizona to investigate the role of eosinophils and type 2 immune responses in acute lung injury and acute respiratory distress syndrome (ALI/ARDS). The research aims to define how increasing type 2 immune responses of eosinophils through IL-33 activation or suppression of the IRF1...
This $693,942 National Institutes of Health National Heart Lung and Blood Institute Project Grant funds research at Northwestern University aimed at elucidating epigenetic modifiers of regulatory T cell function following viral pneumonia. The goal is to establish causal links between DNA methyltransferase activity, the DNMT adapter UHRF1, and DNA hypermethylation signatures in regulatory T cells during aging and their impaired reparative function after severe viral pneumonia. Through three...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 - Allergy and Infectious Diseases Research) provides $200,016 to The Regents of the University of California, San Francisco (UCSF) to conduct a 5-year research program focused on elucidating the mechanisms by which certain children develop critical illness from SARS-CoV-2 infection. The key objectives are to: 1) Define and characterize the autoantibody repertoire in children with severe...
The National Institute of Allergy and Infectious Diseases (NIAID) awarded a $188,544 Project Grant under the Allergy and Infectious Diseases Research program (CFDA 93.855) to The University of Iowa. The grant will fund research to better understand the molecular mechanisms underlying SARS-CoV-2 infection and innate immune regulation. Specifically, the project aims to examine the role of the protein SAMHD1 in regulating SARS-CoV-2-induced inflammation in primary human airway epithelial cell...
This federal Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI), under the Cardiovascular Diseases Research program (CFDA 93.837), is providing $1,147,992 to The Regents of the University of California, San Francisco (UCSF) to conduct research aimed at advancing precision medicine for acute respiratory distress syndrome (ARDS) and sepsis. The key focus is on deeply phenotyping human samples to understand the functional immune response and pathogen drivers of...
REGULATION OF PATHOLOGIC INFLAMMASOME RESPONSES TO SARS-COV-2 - PROJECT SUMMARY ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CAUSES COVID-19 FATALITIES AND IS LINKED TO UNCONTROLLED RELEASE OF PRO-INFLAMMATORY CYTOKINES, INCLUDING INTERLEUKIN (IL)-1, IL-6, AND TUMOR NECROSIS FACTOR (TNF). BLOCKADE OF IL-1/IL-6 RECEPTOR SIGNALING HAS SHOWN SUCCESS IN TREATING SEVERE COVID-19, BUT THE MOLECULAR CUES INITIATING EXCESSIVE PRODUCTION OF THESE CYTOKINES REMAINS UNCLEAR. A MAJOR SOURCE OF IL-1 IS THE INFLAMMASOME, A SUPRAMOLECULAR PROTEIN COMPLEX FORMED IN RESPONSE TO TWO INNATE IMMUNE STIMULI THAT EXECUTES IL-1B RELEASE. META-ANALYSIS OF PATIENT SINGLE-CELL RNA SEQUENCING DATA REVEALS EXACERBATED EXPRESSION OF IL1B AND INFLAMMASOME-RELATED GENES IN SEVERE, BUT NOT MILD, COVID-19. CO-CULTURE OF PRIMARY HUMAN AIRWAY EPITHELIA (HAE) AND PRIMARY HUMAN LEUKOCYTES DURING SARS-COV-2 INFECTION PROMOTES IL-1B RELEASE, WHILE INFECTION IN EITHER CELL TYPE ALONE DOES NOT. THESE CONDITIONS ALSO PROMOTE IL-6 RELEASE IN AN IL-1-DEPENDENT MANNER, HIGHLIGHTING HOW INFLAMMASOME ACTIVATION AND CELL-CELL COMMUNICATION AMPLIFY THIS INFLAMMATORY RESPONSE. FURTHERMORE, INFECTED HAE UNDERGO LYTIC CELL DEATH AND SECRETE INFLAMMASOME-ACTIVATING DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS). THEREFORE, THE SCIENTIFIC GOAL OF THIS PROPOSAL IS TO UNDERSTAND HOW SARS-COV-2 INFECTION PROMOTES PATHOLOGIC INFLAMMASOME RESPONSES WITH THE CENTRAL HYPOTHESIS THAT DAMAGE FROM DYING, INFECTED AIRWAY EPITHELIAL CELLS POTENTIATE DETRIMENTAL IL-1B RELEASE. AIM 1 WILL DETERMINE WHICH INFLAMMASOME(S) MEDIATE HARMFUL IL-1B RESPONSES DURING SARS-COV-2 INFECTION IN VIVO AND IDENTIFY THE TISSUE(S) FROM WHICH THIS RESPONSE IS DERIVED. AIM 2 WILL DEFINE THE MECHANISM OF SARS-COV-2-MEDIATED CELL DEATH IN AIRWAY EPITHELIAL CELLS AND ITS RELATIONSHIP WITH INFLAMMASOME-MEDIATED CELL DEATH IN MYELOID CELLS USING AN ESTABLISHED PRIMARY HUMAN CO-CULTURE SYSTEM. AIM 3 WILL IDENTIFY DAMPS RELEASED BY INFECTED PRIMARY HUMAN AIRWAY EPITHELIAL CELLS THAT STIMULATE INFLAMMASOME RESPONSE VIA AN UNBIASED MULTI-OMICS APPROACH. THESE STUDIES WILL DEFINE HOW DAMAGE CAUSED BY VIRAL INFECTION PROPAGATES INFLAMMATION AND ITS ROLE IN DISEASE, OPENING AVENUES FOR THERAPEUTIC TARGETING AND IDENTIFYING BIOMARKERS RELATED TO PATHOLOGIC INFLAMMATION IN COVID-19. MY GOAL IS TO BECOME A TENURED FACULTY MEMBER AT A MAJOR RESEARCH UNIVERSITY WITH A RESEARCH PROGRAM STUDYING FATAL AND EMERGING VIRAL PATHOGENS. MY GROUP WILL FOCUS ITS EFFORTS ON UNDERSTANDING THE INNATE IMMUNE RESPONSE TO VIRUSES THAT REGULARLY THREATEN HUMAN HEALTH AND PINPOINT PATTERN RECOGNITION RECEPTOR (PRR) LIGANDS THAT LEAD TO DETRIMENTAL PATIENT OUTCOMES. USING A COMBINED APPROACH OF PRIMARY HUMAN CELL CULTURE MODELS, ORGANISMAL MURINE MODELS, AND MECHANISTIC MOLECULAR BIOLOGY, I WILL IDENTIFY READILY TRANSLATABLE MOLECULAR TARGETS TO TREAT HUMAN VIRAL DISEASES. HEREIN, I OUTLINE BOTH A SCIENTIFIC VISION AND A PLAN ACQUIRE NEW SKILLS THROUGH COLLABORATION WITH LOCAL FACULTY, THE SUPPORT OF MY COMMUNITY AND MY ADVISORY COMMITTEE, AND FORMAL COURSEWORK TO ENHANCE MY ABILITIES FURTHER, CREATING A FRAMEWORK FOR MY SUCCESS AS AN INDEPENDENT INVESTIGATOR.