R01AI189410

MACROPHAGE SENESCENCE AS A DRIVER OF GRANULOMA FAILURE AND PROGRESSION TO NECROSIS IN TB AND TB/HIV - ABSTRACT UNDERSTANDING THE FUNDAMENTAL MECHANISMS OF GRANULOMA BREAKDOWN AND NECROSIS IN PULMONARY TB LESIONS IS A KEY UNMET NEED. LUNG GRANULOMATOUS LESIONS FROM HUMAN ACTIVE TB LUNG LESIONS SHOW PROMINENT MARKERS OF CELLULAR SENESCENCE IN MYELOID CELLS, BUT THIS ASPECT OF GRANULOMA BREAKDOWN HAS NOT BEEN WELL-STUDIED. IN THE B6.SST1S MOUSE MODEL (WHERE GRANULOMA FAILURE ALSO LEADS TO NECROSIS) WE HAVE IDENTIFIED MULTIPLE SENESCENCE MARKERS ANALOGOUS TO THOSE SEEN IN HUMAN TB. SENESCENT CELLS ARE NON-REPLICATING, LONG-LIVED CELLS WHICH RELEASE SIGNALING MOLECULES (CALLED THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE, SASP) THAT ARE LOCALLY DELETERIOUS AND PROMOTE TISSUE DYSFUNCTION. OUR CENTRAL PREMISE IS THAT NON-CONTROLLING GRANULOMAS (BOTH IN PREDISPOSED HUMANS AND IN THE B6.SST1S MODEL) ADOPT A STRESS-INDUCED SENESCENCE (SIS) PHENOTYPE DURING MTB INFECTION DRIVEN BY (I) LIPID PEROXIDATION, (II) MYC ACTIVATION, AND (III) UNRESOLVING PROTEOTOXIC STRESS. THESE SIS MS ARE (I) IMMUNOSUPPRESSIVE (MDSC-LIKE), (II) LONG-LIVED AND RESISTANT TO EARLY DEATH, AND (III) EMIT DELETERIOUS SIGNALS (EG SASP MOLECULES) THAT INHIBIT T CELL ACTIVATION AND PROMOTE RECRUITMENT OF PMNS AND IMMATURE MS. OUR DATA SHOW THAT SIS-MS DISPLAY A MYC-DRIVEN PHENOTYPE WITH OXIDATIVE STRESS, DYSREGULATED PROTEOSTASIS, AND HYPERACTIVITY OF THE IFN-I PATHWAY. THIS FUELS A SELF-SUSTAINED, ESCALATING CYCLE THAT LEADS TO NECROSIS OCCURS VIA A COMBINATION OF FERROPTOTIC-LIKE DEATH OF SIS MS AND PMN-MEDIATED DAMAGE. UNDERSCORING THE FACT THAT SENESCENT CELLS PLAY A CAUSAL ROLE IN TB PROGRESSION, WE RECENTLY FOUND THAT A 3-DRUG COCKTAIL OF SENOLYTIC DRUGS (DASATINIB D, QUERCETIN Q, AND FISETIN F)--DESIGNED TO KILL THE DELETERIOUS SENESCENT CELLS-- SIGNIFICANTLY REDUCES LUNG CFU COUNTS AND PROLONGS SURVIVAL IN MTB-INFECTED B6.SST1S MICE. THUS, STUDIES OF SENESCENCE IN TB MAY OFFER A SIGNIFICANT CLINICAL PAYOFF IN THE FORM OF NOVEL HOST-DIRECTED THERAPIES (HDT) FOR TB. [NEW] IN THIS APPLICATION WE WILL ESTABLISH A DETAILED TEMPORO-SPATIAL UNDERSTANDING OF SIS-MS AND SURROUNDING CELLS USING SPATIAL TRANSCRIPTOMIC IN 2 SPECIES THAT PROGRESS TO NECROTIC TB: B6.SST1S MICE AND WT RABBITS (AIM 1). WE WILL EXPLOIT THE NEW FINDING OF SUCCESSFUL HDT ACTIVITY BY A COCKTAIL OF 3 SENOLYTIC DRUGS BY OPTIMIZING THE 3 DRUGS AND THEIR INTERACTIONS WITH STD-TX (AIM 2). WE WILL ALSO EXPLORE THE SENESCENCE-DRIVEN PATHOLOGIC PATHWAYS IN THE SETTING OF TB-SIV CO-INFECTION USING NON-HUMAN PRIMATES (AIM 3).

The Johns Hopkins University

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]

Baltimore, Maryland 212051832 United States

Single Zip Code

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