Advancements in longevity and later-life quality are hampered greatly by the progressive failure of the human immune system which protects the host from infections and malignancies. Loss of protective immunity is associated with the gain of a chronic, smoldering inflammatory syndrome. Molecular mechanisms underlying aging-induced immune deterioration are insufficiently understood. The process of immune aging is accelerated in patients with the autoimmune syndrome rheumatoid arthritis (RA) by about 25 years and these patients are at higher risk for age-related morbidities, such as cardiovascular disease. Telomeres in T cells from RA patients are age-inappropriately shortened;but, more importantly, some chromosomes have telomere-free ends and undergo telomeric fusions. This phenotype of telomeric damage is related to ineffectiveness of the ATR-Chk1 DNA repair pathway. In RA T cells and in T cells from individuals >75 years, telomeres carry an increased load of ATR, yet binding of TopBP1, an indispensible activator of ATR, is diminished. This proposal is designed to understand on a mechanistic level the DNA damage responses emanating from damaged telomeres, how they contribute to the process of immune aging and how telomeric damage biases T cells away from protective immunity towards inflammation.
In Specific Aim 1, we will define the molecular components of the DNA damage response at stressed telomeres in young and old T cells. We will proceed in Specific Aim 2 to examine how progressive age and the inflammatory status of the host affect telomeric damage repair and the resulting cellular response. These experiments will build on two study cohorts;the Healthy Aging, Lifestyle and Frailty (HALF) cohort composed of healthy individuals aged 30-90 years and the Stanford Rheumatoid Arthritis (STAR) cohort, a prospective cohort of patients with rheumatoid arthritis. We will quantify the telomeric TopBP1-ATR module in relation to advancing age and RA disease burden.
Specific Aim 3 will reveal the consequences of telomeric damage on T cell fate, clonal expansion and functional commitment. By setting intentional telomere damage we will study the impact of the telomere- dependent damage machinery on T cell apoptosis and commitment to the Th1, Th2, Th17, Tfh and Treg lineage. Also, we will explore whether telomere damage correlates with effectiveness of an influenza vaccine in the elderly.
In Specific Aim 4, we will explore the role of telomeric uncapping on the immune aging process in vivo and build a preclinical testing platform for therapeutic interventions aimed at slowing T cell aging. These experiments rely on the reconstitution of immunodeficient mice with human T cells to measure their homeostatic expansion, their apoptotic susceptibility and their na?ve-to-memory conversion. Overall, this proposal promises to provide new understanding of the molecular events that occur at aging telomeres and to utilize that knowledge to develop novel therapeutic strategies to combat immune aging.

Public Health Relevance

Aging of the immune system renders individuals susceptible to infections and cancer and induces a state of subclinical inflammation injurious to many tissues;a process that is accelerated in the autoimmune syndrome rheumatoid arthritis. Aging of immune cells leaves the telomeres at the ends of chromosomes shortened and frizzled. This proposal aims to understand why telomere damage occurs, how cells respond to their damaged telomeres and how this process can be exploited for novel therapies to slow down, and eventually revert, the aging of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI108906-01
Application #
8623563
Study Section
Special Emphasis Panel (ZAI1-LAR-I (S1))
Program Officer
Prabhudas, Mercy R
Project Start
2013-12-20
Project End
2018-11-30
Budget Start
2013-12-20
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$434,419
Indirect Cost
$167,483
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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