P01AI186771

Novel mechanisms of genetic errors of immunity - Project summary:

Inborn errors of immunity (IEI) collectively comprise more than 500 different monogenic disorders of the immune system.

Primary immune regulation disorders (PIRD) represent a subset of IEI, that are characterized clinically by a lack of regulation of the immune response resulting in overlapping features of infectious susceptibility, autoimmunity, lymphoproliferation, inflammation, and/or atopy.

While tremendous advances in patient diagnosis and disease mechanisms understanding have been made, significant gaps in the field remain.

First, the molecular diagnostic rate for all IEI remains only 30-40%, even in multiplex families with high likelihood of genetic inheritance.

Second, most diseases of immune dysregulation have variable penetrance (i.e., have or don’t have disease) and have variable expressivity (i.e., have mild vs severe disease).

This phenomenon is by and large unexplained.

Our emerging data suggests three evolving genetic concepts of disease including epigenetic, somatic mutations, and genetic modifiers.

We propose to use the term genetic errors of immunity (GEIs) to encompass these broad and novel molecular mechanisms.

In Project 1 we will tackle a novel epigenetic mechanism, where despite heterozygosity on DNA level, transcriptionally only one allele is expressed in select cell lineages, a phenomenon termed autosomal random monoallelic expression (ARMAE).

We propose to map genes that are prone to ARMAE in the immune system, define epigenetic marks governing this process, and validate these findings in individuals with identified genetic lesions within families with known incomplete penetrance.

This will allow us to document discrepant genotype to “transcriptotype” and measure functional implication of this epigenetic phenomenon.

In Project 2 we will investigate somatic mutations as a cause of GEIs, a concept in its infancy.

Herein we propose to perform high-depth targeted sequencing to identify genetic mosaicism in patients with suspected GEI who were negative by standard genetic testing, and to develop single cell technologies for evaluating their functional impact on the immune response.

Our preliminary data suggests that a mutation causative of PIRD can be both somatic and in a gene undergoing ARMAE, suggesting clear synergy among Project 1 and Project 2.

Finally, in Project 3, we will address known genetic risk variants in tandem with polygenic risk score (both of which would otherwise be clinically silent).

This concept is of great interest in the IEI field.

Understanding these modifier genes, whether germline, somatic or epigenetically regulated (undergoing ARMAE) forms a clear cohesive connection between Projects 1-3.

To support this set of integrated yet distinct projects we propose:

1) An administrative core charged with coordination of meetings, regulatory compliance, and grant management;

2) Sequencing and sample core: tasked with patient and control sample WEG, WGS, targeted deep sequencing, RNA seq, and scRNAseq; and

3) Bioinformatics and computational biology core tasked with development and integration of bioinformatic pipelines.

Combined, these 3 projects and 3 cores will synergize in defining novel disease mechanisms in GEI.

Washington 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]

Saint Louis, Missouri 63130 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 100% from $2,483,910 to $4,967,820.