P01AI172501

The role of senescent cells in dysregulating immune responses and pathogen control - summary
The association between advanced age and impaired resistance to infections is well known, but poorly understood.
The current COVID-19 pandemic is a clear example of the vulnerability of the elderly to SARS- CoV-2 infection as well as many other pathogens.

Considerable research efforts have shown that components of both the innate and adaptive immune systems show signs of dysfunction as we age, with signs of both immunodeficiency, including reduced innate response and poor induction of adaptive immune memory, and immunopathology including an exaggerated “cytokine storm”.
However, while aspects of age-related changes in immune cells have been explored in depth, the focus has been on defining the nature of dysfunction within cells of the immune system itself, rather than investigating the potential role of other cell populations in dominantly compromising immune homeostasis and immunological response to pathogens.
Also, although the increase in immunosenescence with age, defined by cell surface markers for immune cell exhaustion, has been examined, the extent of cellular senescence in immune cell populations with age and pathogen exposure remains undefined.

Our recent findings indicate that senescent cells (SNCs), including senescent immune cells, can exert a “bystander” effect on immune cells, provoking immunological dysfunction through secretion of inflammatory factors, including cytokines and chemokines, termed the “senescence-associated secretory phenotype” (SASP).
We demonstrated that SASP factor production is increased when SNCs or mice containing SNCs are exposed to pathogens or microbial products that induce innate immune activation.
Exposure of old mice to normal microbial experience (NME) housing resulted in 100% mortality compared to no mortality in young mice.

However, reducing the senescent cell burden in aged mice before or following pathogen exposure reduced the spread of senescence, the cytokine storm and overall mortality.
These results suggest that SNCs, acting at least in part through SASP factors, can increase peripheral senescence and immune dysfunction following pathogen exposure.
Moreover, viral infection itself drives senescence, termed virus induced senescence, in mice and humans.

Using mouse models in which cellular senescence is induced specifically in immune cells, we also demonstrated that senescent immune cells drive immunological dysfunction and secondary senescence and pathology in non-lymphoid tissues.
Thus, our overarching hypothesis is that senescent cells, including senescent immune cell types, dominantly compromise innate and adaptive immune cell homeostasis in both lymphoid and non-lymphoid organs and reactivity to pathogens.

Importantly, we also hypothesize that these adverse effects can be reversed by SNC elimination with senolytics, providing a new therapeutic strategy to restoring immune function in the aged.
We propose to test these hypotheses in our PPG application entitled “The Role of Senescent Cells in Dysregulating Immune Responses and Pathogen Control”, consisting of three collaborative projects and three integrated cores.

Regents Of The University Of Minnesota

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]

Minneapolis, Minnesota 554553008 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 99% from $2,723,166 to $5,432,276.