Proteostasis and Senescence in Asthma and Aging
Description: An increasing elderly population at higher risk and vulnerability to lung diseases such as asthma necessitates understanding mechanisms contributing to structural and functional changes in aging airways. I propose that aging airways (particularly in asthma of elderly (AIE)) undergo greater remodeling (fibrosis, cell proliferation). I propose to explore airway mesenchymal cells (airway smooth muscle (ASM) and fibroblasts (FBs)) using samples from patients across the age spectrum with vs. without asthma. I hypothesize that aging enhances endoplasmic reticulum (ER) stress (but impairs unfolded protein response; UPR), promotes mitochondrial fragmentation and dysfunction: factors that promote cellular senescence in ASM and FBs. Senescent cells develop a senescence-associated secretory profile (SASP) that includes inflammatory cytokines (e.g. IL-6). I propose that ASM and FB SASP enhances proliferation and fibrosis via autocrine/paracrine effects, and synergizes ER stress, UPR, and mitochondrial changes in a feed-forward way to promote remodeling: processes exaggerated in AIE. My specific aims are: Aim 1: Determine aging- and AIE-associated changes in ER stress, UPR, and mitochondria in the context of senescence and remodeling in human ASM and FBs. I will utilize ASM and FBs from non-asthmatics vs. moderate asthmatics in 3 age groups (young (<45y), middle-aged (45-65y), and elderly (>65y)) and explore molecular changes in aging ASM and FBs that drive a fibrotic phenotype, focusing on ER stress, UPR, mitochondrial structure and metabolism, senescence/SASP and remodeling. Techniques learned include RNA sequencing, RT-PCR, Westerns, ELISA, imaging, and Seahorse measurements. Age- and AIE-related changes in fibrotic features are validated in lung sections using laser capture microdissection and IHC/IF. Aim 2: Determine mechanistic contributions of human ASM and FB ER stress, UPR, mitochondria and senescence in enhanced remodeling of aging vs. AIE. Using pharmacological tools, si/shRNA, overexpression vectors and techniques of Aim 1, I will link the molecular changes in Aim 1 to functional aspects such as fibrosis and proliferation of aging and asthmatic ASM and FBs. Overall, my studies will prepare me in developing a niche in pulmonary diseases of the elderly, setting the stage for my planned K99/R00, and will guide future therapeutic strategies for elderly asthmatics who show poor responses to current therapies.
Funder: American Heart Association
Amount: $104,100
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2019-01-01
End date: 2020-12-31
Investigators: Sarah Wicher, Sarah Wicher
Institution: MAYO CLINIC, ROCHESTER, MN
Funded outputs count: 4
Funder award ID: 19POST34430017
OpenAlex ID: G2910744087