R01AI166835

Mechanistic and functional dissection of inflammaging in Down Syndrome - Project Summary/Abstract

The immune system becomes functionally impaired with aging (inflammaging), impacting risk and outcome of infection, vaccination, cancer, cardiovascular disease, and autoimmunity. Individuals with Down Syndrome (DS) exhibit clinical, cellular, and biochemical features of inflammaging, including increased autoimmunity, decreased naïve T cells, and increased pro-inflammatory cytokines.

We developed a novel unbiased approach to analyze immune architecture in people with DS and quantitatively showed that people with DS exhibit advanced immune aging beginning in childhood driven in part by dysregulation of naïve CD4+ T cells. This approach showed shared features of advanced immune aging in DS and other autoimmune diseases, suggesting functional relevance and overlap.

Therefore, understanding (i) how advanced immune aging explains impaired functional immune responses in DS, and (ii) how dysregulation of naïve CD4+ T cells contributes to advanced immune aging, will help us develop novel therapeutic strategies to address immune defects in DS. Moreover, this understanding will help us identify subsets of the general population who may benefit from similar therapeutic strategies. This also establishes a basis to understand which genes on chromosome 21 drive advanced immune aging, with attendant mechanistic and translational implications.

We hypothesize that advanced immune aging impairs immune responses by dysregulating naïve CD4+ T cells via cell-intrinsic and cell-extrinsic pathways. We propose key experiments here to advance our understanding of immune aging and immune response in DS. Our specific aims are:

1: Dissecting mechanistic features of naïve CD4+ T cell dysregulation in DS-inflammaging. We will leverage a novel DS biorepository that I helped establish at BRI to examine how DS impacts CD4+ T cell biology in the absence of confounding immune disorders. We will use in vitro assays coupled with RNAseq to identify and test candidate mechanisms. We will study individuals with mosaic DS to provide unique insight to dissect the cell-intrinsic roles of trisomy 21 in CD4+ T cell dysregulation in vivo.

2: Interrogate phenotypic and functional features of DS-inflammaging in vivo. We will use our immune cellular clock to quantitatively understand how inflammaging impacts vaccine response in people with DS and controls. We will also examine robustness of our DS-inflammaging findings in an independent cohort and follow our original cohort longitudinally to evaluate temporal progression of DS-inflammaging.

Benaroya Research Institute At Virginia Mason

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.

93.310 - Trans-NIH Research Support

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Seattle, Washington 981012795 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 367% from $677,851 to $3,165,277.