R01AI187249

ROLE OF THE CELL DEATH MACHINERY IN A SOMATIC AUTOINFLAMMATORY SYNDROME - PROJECT SUMMARY THE AUTOINFLAMMATORY SYNDROMES ARE A GROUP OF GENETIC DISEASES OFTEN CAUSED BY DEFECTS IN INNATE IMMUNE GENES. IN DECEMBER 2020, A NOVEL SOMATICALLY ACQUIRED AUTOINFLAMMATORY SYNDROME TERMED VEXAS (VACUOLES, E1-UBIQUITIN-ACTIVATING ENZYME, X-LINKED, AUTOINFLAMMATORY, SOMATIC) WAS REPORTED. VEXAS IS CAUSED BY SOMATIC MUTATIONS IN THE UBIQUITIN-ACTIVATING ENZYME UBA1, MOST OF WHICH OCCUR AT AN INTERNAL TRANSLATION START SITE (MET41). AS UBA1 IS X-LINKED, VEXAS PRIMARILY AFFECTS MALES WHO MOSAICALLY HARBOR UBA1 MUTATIONS IN HEMATOPOIETIC STEM AND PROGENITOR CELLS AND THEIR MYELOID, BUT NOT LYMPHOID, PROGENY. THESE PATIENTS DEVELOP A CONSTELLATION OF CLINICAL SEQUELAE, INCLUDING HEMATOLOGIC ABNORMALITIES, RECURRENT FEVERS, ARTHRITIS, AND SKIN AND LUNG INFLAMMATION. AS A RESULT, PATIENTS MAY REQUIRE ALLOGENEIC BONE MARROW TRANSPLANTATION AND SUFFER SIGNIFICANT MORBIDITY AND MORTALITY. CURRENTLY, OUR MOLECULAR AND CELLULAR UNDERSTANDING OF VEXAS PATHOGENESIS IS LIMITED BY A LACK OF EXPERIMENTAL MODEL SYSTEMS. TO ADDRESS THIS, WE DEPLOY AN ADENINE BASE-EDITING SYSTEM TO RECREATE ONE OF THE MOST COMMON VEXAS MUTATIONS IN MOUSE OR HUMAN MACROPHAGES AND HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). USING THIS SYSTEM, WE HAVE FOUND THAT MOUSE AND HUMAN MACROPHAGES WITH A VEXAS-ASSOCIATED UBA 1 MUTATION UNDERGO ABERRANT CELL DEATH DURING RESPONSES TO TUMOR NECROSIS FACTOR (TNF) OR LIPOPOLYSACCHARIDE (LPS, A TOLL-LIKE RECEPTOR (TLR)4 LIGAND), AND THAT VEXAS HSPCS SPONTANEOUSLY DIFFERENTIATE INTO MYELOID CELLS. THESE CELLULAR PHENOTYPES CORRELATE WITH KEY ASPECTS OF VEXAS PATHOGENESIS IN HUMANS (I.E. AUTOINFLAMMATION AND MYELOID EXPANSION) AND THEREBY OFFER A PLATFORM FOR DECIPHERING DISEASE- DRIVING MECHANISMS. IN AIM 1, WE WILL USE THIS NEWLY DEVELOPED CELL SYSTEM TO DETERMINE THE MECHANISMS OF TNF- AND TLR4-DRIVEN CELL DEATH IN MACROPHAGES CARRYING A VEXAS-ASSOCIATED UBA1 MUTATION. IN AIM 2, WE WILL INVESTIGATE THE ROLE OF UBIQUITIN-DEPENDENT SIGNALING IN THIS CELL DEATH PHENOTYPE. IN AIM 3, WE WILL ELUCIDATE MECHANISMS UNDERLYING THE SPONTANEOUS MYELOID DIFFERENTIATION OF HSPCS WITH A VEXAS-ASSOCIATED UBA1 MUTATION. IF SUCCESSFUL, OUR PROPOSAL PROMISES TO YIELD FUNDAMENTAL INSIGHTS INTO A DEVASTATING AUTOINFLAMMATORY DISEASE WITH POTENTIAL IMPLICATIONS FOR UNDERSTANDING THE INTERRELATIONSHIPS BETWEEN CLONAL HEMATOPOIESIS AND INFLAMMATION.

Sloan-Kettering Institute For Cancer Research

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)