U19AI162310

INTEGRATED GENETIC, OMIC, AND IMMUNOLOGIC STUDIES TO IDENTIFY ENDOTYPES AND NOVEL DRUG TARGETS FOR ASTHMA AND ALLERGIC DISEASES - ABSTRACT

ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST COMMON CHRONIC DISEASES IN CHILDREN AND ADULTS, COSTING OUR HEALTH CARE SYSTEM OVER $80 BILLION PER YEAR. RATES HAVE BEEN INCREASING OVER THE PAST 40 YEARS AND THERAPEUTIC ADVANCES HAVE BEEN INCREMENTAL.

OVER 150 LOCI HAVE BEEN REPORTED IN LARGE GENOME-WIDE ASSOCIATION STUDIES (GWAS) OF ASTHMA AND ALLERGIC DISEASES, BUT THEIR INDIVIDUAL EFFECTS ARE SMALL AND THESE VARIANTS ACCOUNT A SMALL FRACTION OF THE OVERALL GENETIC RISK. MOREOVER, REMARKABLY FEW OF THE GWAS FINDINGS FOR ASTHMA AND ALLERGIC DISEASES HAVE LED TO DISCOVERIES OF CAUSAL VARIANTS OR CAUSAL GENES THAT CONTRIBUTE TO ASTHMA AND ALLERGIC DISEASE PATHOGENESIS.

THE LATTER HAS BEEN PARTICULARLY CHALLENGING DUE IN PART TO THE SIGNIFICANT CLINICAL HETEROGENEITY OF THESE DISEASES, AND IN PART TO THE LAG IN THE DEVELOPMENT OF POWERFUL STATISTICAL, MOLECULAR, AND IMMUNOLOGIC TOOLS FOR BRIDGING THE TRAJECTORY FROM GWAS TO GENE DISCOVERY TO BIOLOGY TO TRANSLATION.

IN THIS APPLICATION, WE PROPOSE A ROBUST AND COMPREHENSIVE STRATEGY FOR IDENTIFYING CANDIDATE CAUSAL VARIANTS AND THEIR TARGET GENES AT ASTHMA AND ALLERGIC DISEASE-ASSOCIATED LOCI, AND FOR CHARACTERIZING (I) THEIR FUNCTIONAL EFFECTS IN ASTHMA AND ALLERGIC DISEASE-RELEVANT CELLS TYPES, INCLUDING BRONCHIAL EPITHELIAL CELLS, AIRWAY SMOOTH MUSCLE AND LUNG IMMUNE CELLS, AS WELL AS PERIPHERAL IMMUNE CELLS, ALL IN RESTING AND ACTIVATED STATES; (II) THEIR DOWNSTREAM PHENOTYPIC EFFECTS ON BOTH BROAD CATEGORIES OF DISEASE GROUPS AND TRAITS IN THE UK BIOBANK RESOURCE AND ON SPECIFIC ASTHMA AND ALLERGIC DISEASE ENDOTYPES IN DEEPLY PHENOTYPED ETHNICALLY-DIVERSE SUBJECTS PARTICIPATING IN ASTHMA BIRTH COHORTS; AND (III) THEIR IMMUNOLOGIC EFFECTS IN RESTING AND ACTIVATED LUNG LYMPHOCYTES AND MYELOID CELLS AND IN “HUMANIZED LOCUS” BAC-ENGINEERED MOUSE MODELS.

THESE GOALS WILL BE ACCOMPLISHED THROUGH A HIGHLY COLLABORATIVE AND SYNERGISTIC PROGRAM THAT INCLUDES TWO PROJECTS, A SERVICE CORE, AND AN ADMINISTRATIVE CORE THAT TOGETHER WILL THAT BRIDGE THE TRAJECTORY FROM GWAS TO TRANSLATION THROUGH HIGHLY INTEGRATED STUDIES BY AN EXCEPTIONAL TEAM OF INVESTIGATORS WITH EXPERTISE IN GENETICS, (EPI)GENOMICS, STATISTICAL GENETICS, AND IMMUNOLOGY.

ACHIEVING THESE GOALS WILL ULTIMATELY IDENTIFY NOVEL DRUG TARGETS AND THE INDIVIDUALS MOST LIKELY TO RESPOND, PROVIDING A FRAMEWORK FOR PRECISION MEDICINE AND PERSONALIZED TREATMENT OF ASTHMA AND ALLERGIC DISEASES.

University Of Chicago

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]

Chicago, Illinois 606375418 United States

Single Zip Code

Asthma and Allergic Diseases Cooperative Research Centers (U19 Clinical Trial Optional) (RFA-AI-20-007)

Amendment Since initial award the total obligations have increased 459% from $1,391,652 to $7,775,155.