P01AI179406

Understanding the molecular mechanisms regulating fungal colonization and disease in the mammalian intestinal niche - project summary. The Fungal Colonization Resistance (FUNCORE) program project “Understanding the molecular mechanisms regulating fungal colonization and disease in the mammalian intestinal niche” focuses on developing an integrated and predictive model of the molecular, cellular, and metabolic determinants of Candida gastrointestinal (GI) colonization and its relationship to life-threatening invasive candidiasis. FUNCORE consists of 3 projects and 3 cores and combines in-depth studies of hematopoietic cell transplant patients with defined Candida colonization phenotypes and curated clinical data with experiments in reductionist experimental models of Candida GI colonization.

The patient cohort serves as a source for a large Candida strain collection and for fecal metabolite abundance measurements that are harnessed in projects and cores. Project 1 emphasizes the role of morphology, virulence factors, and strain-specific genomic features on C. albicans and C. parapsilosis GI colonization. Project 2 characterizes immune signaling pathways and cell types (Paneth cells, innate lymphoid cells) that mediate Candida colonization resistance. Project 3 focuses on the bacterial microbiota and their biosynthetic capabilities, with a focus on short- and medium-chain fatty acids, to determine direct and indirect mechanisms of colonization resistance.

A gnotobiotic core enables deep mechanistic dissection of the contribution of individual molecular, cellular, immune pathways, and commensal bacteria to colonization phenotypes. A mathematical modeling core ties all 3 projects together and will generate predictive models of Candida GI colonization that incorporate specific fungal attributes, the bacterial microbiota and metabolites, and host immune parameters. Modeling outputs will be iteratively tested and refined in collaboration with the experimental projects to explore the overall hypothesis that the synergy of experimental and modeling approaches will reveal fungal, immune-mediated, and metabolic determinants of Candida GI colonization and colonization resistance which can inform and be harnessed for therapeutic strategies to limit invasive candidiasis.

Aim 1 will investigate the Candida functional capacities that promote GI colonization; Aim 2 will interrogate host cell networks and colonization-relevant metabolites at the host-Candida interface; Aim 3 will develop an integrative model of Candida colonization resistance that identifies ecologic, immune, and metabolic targets to restore and enhance Candida colonization resistance. Successful completion of these aims will be supported by a strong administrative core management plan to facilitate communication and collaboration between projects and cores. The breadth and complementarity of expertise, multidisciplinary approaches, track record of collaboration, and commitment to establish a mentored undergraduate internship program represent signature features of FUNCORE.

Insights will inform benchtop-to-bed strategies to formulate novel interventions that can shape the fungal communities in the GI niche to prevent invasive candidiasis and improve patient outcomes.

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, New York 100656007 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-22-225)

Amendment Since initial award the total obligations have increased 97% from $2,527,410 to $4,977,820.