U19AI162583

Host Pathogen Variation & TB Pathogenesis - Hurdles for Controlling Tuberculosis (TB) include developing a highly efficacious vaccine, preventing transmission and infection in endemic areas, and discovering drug treatment regimens that work rapidly and kill dormant bacilli within macrophages.

After exposure to Mycobacterium tuberculosis (MTB), outcomes vary widely including resistance, asymptomatic latent infection, active pulmonary disease, and disseminated infections including TB meningitis (TBM). This heterogeneity complicates clinical treatment decisions with regards to choosing the number of drugs and duration of treatment. This broad clinical spectrum also presents a unique opportunity for understanding the biological mechanisms that control TB pathogenesis.

A major source of heterogeneity is a combination of genetic variation in both humans and MTB that are evolving under constant selective pressure. Our overall program objective is to use genetic, genomic, proteomic, and bioinformatic strategies to discover host and pathogen variants of genes and gene products that are associated with TB clinical outcomes and to determine how these variants interact to regulate molecular, cellular, and in vivo functions.

Our strategy is anchored upon two powerful cohorts in Vietnam and Uganda (Core A) that capture the full spectrum of resistance to traditional LTBI (latent TB infection), LTBI, pulmonary TB disease, and disseminated disease in the form of TBM. Core A examines paired host and MTB genetic data and the association with these diverse clinical outcomes.

In Project 1, we use genetic and new proteomic strategies to examine how the MTB genes and variants identified by Core A function and how the encoded proteins interact with and regulate macrophage responses.

In Project 2, we use human genetic methods along with proteomic strategies in macrophages to uncover regulatory host genes and variants that are associated with resistance to MTB infection and/or disseminated TB.

In Project 3, we examine in vivo mechanisms of transmission and dissemination that are attributed to specific host genes and pathways and MTB variants, employing a new and powerful mouse model of infection that recapitulates many of the manifestations that occur in human TB.

Core B uses pathway-driven and novel bioinformatics approaches to integrate the genetic results from Core A with the multiple large-scale and diverse datasets to dynamically identify and prioritize pathways and protein networks for functional testing.

Together, this multidisciplinary program and strategy will enable us to test our overall hypothesis that variants of MTB and host genes dictate heterogeneous clinical outcomes and encode factors that interact with and alter innate immune cells. We will use genetic, genomic, proteomic, and bioinformatic strategies to examine variation in MTB and its paired human host to examine mechanisms of resistance and susceptibility to infection and disease with discovery of biomarkers for clinical management and novel immunomodulatory therapies.

University Of Washington

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]

Seattle, Washington 981094766 United States

Single Zip Code

Tuberculosis Research Units (U19 Clinical Trial Optional) (RFA-AI-20-020)

Amendment Since initial award the total obligations have increased 392% from $2,638,886 to $12,986,605.