Mechanisms of impaired wall shear stress mechanotransduction in aging

Project: Research

Investigators

  • Yanna Tian (PI)

Description

Cardiovascular complications represent a major health problem in the aging population, thereby significantly shortening the lifespan. Mechanisms that underlie aging-specific functional and morphological changes in the vasculature remain ill defined. Recent studies raised the possibility that in disease an altered function of arterial mechanosensory complex(s) contributes to pathological changes in the vasculature. In this study hypothesize that aging activates A disintegrin and metalloproteinase, ADAM17, which via an augmented F11R/JAM-A shedding interferes with its role in WSS mechanosensing, thereby causing reduced arterial dilation and inward remodeling. To test this hypothesis two Specific Aims are proposed: Aim 1. Determine the role of ADAM17 and F11R/JAM-A in reduced wall shear stress (WSS)-induced vasodilation in aging. Aim 2. Determine the role of ADAM17 and F11R/JAM-A in aging-related abnormal arterial remodeling. To achieve these aims protocols are proposed to assess the role of ADAM17 in WSS-induced dilation in isolated skeletal muscle arteries in aged mice (30-month old, from NIA colony) and young (12-week old) controls using videomicroscopy and pharmacological approaches. Using adeno-associated virus, ADAM17, wild type F11R/JAM-A or ADAM17 cleavage resistant F11R/JAM-A arterial wall remodeling before and after WSS manipulating interventions, both in vivo and ex vivo artery preparations will be assessed. Should the results support my hypothesis pharmacological targeting of ADAM17-F11R/JAM-A pathway can be considered for therapeutic prevention of aging-related vascular abnormalities.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35211126
Effective start/end date01/01/202012/31/2021
StatusActive