Project Summary
Aging is characterized by a general decline in overall health and a gradual deterioration across multiple
organ systems. However, our understanding of the aging process and whether we can improve health span
remains a topic of active research. One of the hallmarks of aging is cellular senescence, a stress response that
limits the propagation of damaged cells by causing irreversible cell cycle arrest. The DNA damage response is
one of the key events leading to senescence. Cells in early senescence show increased satellite transcription
and centromere instability and dysmorphism, known as the senescence-associated distension of satellites
(SADS). Cyclic GMP-AMP synthase (cGAS) is a cytosolic innate immune sensor that recognizes and responds
to microbial and self-DNA. Cytoplasmic cGAS is essential for the establishment of senescence and the secretion
of inflammatory mediators characteristic of senescence. However, little is known of cGAS deposition and function
in the nucleus. Nuclear cGAS has been reported to inhibit the DNA Damage Response (DDR) via homologous
recombination (HR) in the nucleus and to be enriched at repetitive sequences such as centromeres and long
interspersed nuclear element (LINE) DNA repeats. Despite these recent findings, the question remains whether
cGAS contributes to senescence entry by modulating HR repair and whether cGAS concentration at centromeres
and LINEs plays a role in the formation of SADS in early senescence. To answer these questions, I propose the
following two aims: Aim 1 will determine whether cGAS inhibition of the DDR contributes to cell entry into
senescence. Aim 2 will determine whether cGAS plays a role in SADS formation in senescence. The findings of
this project will provide mechanistic insight on the effect of nuclear cGAS in the DDR and centromere stability,
and its role in the establishment of senescence. Advancing our knowledge of nuclear cGAS can further current
efforts to develop inhibitors of cGAS as potential anti-inflammatory or anti-aging therapy as strategies that extend
healthy lifespan.
This proposal will be the first to examine the relationship between nuclear cGAS and senescence using
cutting edge technology in imaging and unique expertise in its influence at repetitive elements. One of this
fellowship's training goals is to develop the repertoire of skills and body of knowledge for a successful career in
the biology of aging research. The second goal is to gain experience in effectively communicating research in a
variety of settings. To achieve these goals, completion of the proposed research, attending the Gordon Research
Conference, presenting at national and international conferences, and my sponsor's mentoring will ensure the
success of this training plan. Furthermore, this proposal will take place in the excellent environment of the
interdisciplinary and supportive Molecular Biology, Cell Biology, and Biochemistry program at Brown University.
Completion of this research and training plan will move the biology of aging field forward and provide me with
the ideal preparation towards the career goal of leading an independent academic research laboratory.