P01AI165026

Modulation of NOD Strain Diabetes by ENU-Induced Mutations - Project Summary/Abstract

This P01 proposal offers a fresh approach to understanding the genetics of an extremely important polygenic autoimmune disease: Type 1 Diabetes (T1D), which affects nearly three children out of every thousand in North America, and many more around the world.

T1D occurs with variable penetrance in non-obese diabetic (NOD) mice, which exhibit a phenotype remarkably similar to that of human patients. Both environmental and genetic factors determine penetrance, but most of the influential mutations and the genes they affect remain unknown.

We have developed a powerful technology platform that permits instantaneous identification of point mutations that cause phenotype. Using this platform, we have already identified two spontaneous mutations that cause high and low frequency of disease development in the NOD/NCKH and NOD/NCKL sublines, respectively.

Noting that these sublines, isolated by selective breeding over a period of only seven years, had approximately the same mutational distance from one another as one finds in a pedigree of ENU mutagenized mice as compared to the parental reference strain, we performed a pilot study in which mice were mutagenized on the NOD/NCKH background. In a sample of 14 pedigrees, we unambiguously identified twelve ENU-induced mutations with modifying effects on T1D: some accelerating the disease and others suppressing it.

Stressing the precision of these studies, which do not merely identify intervals or candidates, but resolve the exact nucleotide change responsible for T1D modification, we propose to expand our efforts, analyzing 21,000 coding/splicing mutations for modifier effects over a period of five years.

Our preliminary work suggests that T1D is "balanced on a knife's edge" from a genetic point of view. Mutations in many genes are clearly capable of influencing T1D development, since randomly induced coding/splicing mutations affecting approximately 1% of the mouse genome caused unambiguous modifier phenotypes. We expect to identify scores if not hundreds of individual modifier mutations during the period of funding. Some of these will have important new facts to tell us about what it takes to develop T1D.

Concentrating on those modifier mutations that show large effect sizes, may be amenable to targeting with therapeutic drugs, and/or are particularly surprising in light of what we presently know about T1D pathogenesis, we will rigorously verify causation by re-creating the mutations and/or deleting the causative genes on clean backgrounds (NOD/NCKH or NOD/NCKL devoid of ENU-induced mutations).

We will then systematically examine the mechanism of phenotype modification, both at the level of cellular immuno-pathogenesis, and at the level of molecular pathogenesis. Ultimately, we hope to understand how T1D can be prevented or driven into remission, and we expect many new insights to emerge from the studies planned.

A close collaboration between the Bach/Chatenoud group, with its great expertise in the study of T1D pathogenesis in NOD mice, and the Beutler group, with its strength in forward genetics, will contribute to the success of this P01. The core laboratories and projects are exceptionally synergistic, assuring that this P01 will dramatically exceed the sum of its parts.

The University Of Texas Southwestern Medical Center

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]

Dallas, Texas 753907208 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-20-072)

Amendment Since initial award the total obligations have increased 199% from $2,214,936 to $6,612,806.