Project Details
Description
PROJECT SUMMARY
The goals of this proposal are to (1) obtain experimental skills and career training necessary to develop an
independent research program investigating mechanisms of age-dependent cognitive decline and Alzheimer’s
disease pathogenesis and (2) determine whether cellular senescence contributes to cerebrovascular and
cognitive dysfunction. Age-related deterioration of the cerebrovasculature is an important contributor to
cognitive decline and Alzheimer’s disease, but targetable underlying mechanisms have yet to be discovered.
Cellular senescence has emerged as a unifying feature of aging and numerous age-related conditions.
Through the senescence-associated secretory phenotype (SASP), senescent cells impair tissue structure and
function. Despite the well-known relationships between age-related vascular decline and cognition, whether
and how senescent cells and the SASP contribute to cerebrovascular and cognitive dysfunction has not been
explored. The proposed project will use young (6 months) and aged (26 months) p16-Ink-Attac mice, in which
senescent cells can be GFP-monitored or deleted. We will also test the effects of senolytic drugs, which kill
senescent cells. Parallel transgenic and pharmacological elimination strategies will enable us to mechanistical-
ly explore the identity and effects of senescent cells. Aim 1 will identify the cell types that senesce in brain
aging and will compare transgenic and senolytic cell clearance efficiency across cell populations in vivo. Aim 2
will leverage in vivo and in vitro experiments to test the hypothesis that senescent cerebrovascular cells
secrete a proremodeling and proinflammatory SASP, which promotes BBB permeability and inflammation and
may be alleviated by senescent cell clearance. Aim 3 will test the hypothesis that senescent cell removal
improves vasomotor and cognitive function in aged mice. The K99 phase will be conducted at Mayo Clinic and
will focus on obtaining mentored training in methods required to complete the proposed aims, conducting in
vitro and in vivo experiments, and publishing cell-type profiling and in vitro results. The R00 phase will be
conducted in my independent lab and will focus on analyzing mouse tissues and data, publishing all in vivo
findings, and developing an R01 application based on these results. The proposed plan synergizes new skills
in advanced imaging, vascular physiology, and cognitive testing with prior expertise in brain aging and cellular
senescence to create a research trajectory that is distinct from my mentors’ foci. This work will produce a
robust foundation for an independent research career elucidating cellular aging mechanisms and translatable
solutions underlying cognitive decline and Alzheimer’s disease.
Status | Finished |
---|---|
Effective start/end date | 1/1/21 → 12/31/23 |
Funding
- National Institute on Aging: $249,000.00
- National Institute on Aging: $224,103.00
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