Sunday, December 8, 2024
12/8/2024
PROJECT DESCRIPTION The hallmarks of the aging blood system, such as chronic inflammatory disorders, anemia, immunosenescence and hematological malignancies, result in large part from hematopoietic stem cell (HSC) dysfunction. Age-associated loss of HSC function is linked to metabolic deregulation, increased dependence on autophagy, loss of epigenetic fidelity, replication stress-associated genomic instability, and chronic exposure to local inflammation in the aged bone marrow (BM) niche microenvironment. However, these remain largely descriptive features of HSC aging. This project aims to develop a coherent and mechanistic model of how these extrinsic signals and intrinsic molecular mediators promote old HSC dysfunction, ultimately suggesting actionable targets for rejuvenation interventions. In Aim 1, we will test the hypothesis that autophagy engagement is a prosurvival stress-response mechanism that protects a subset of old HSCs from chronic inflammation in the aged BM niche. Specifically, we will probe whether increased oxidative metabolism in old HSCs functions to compensate for decreased glucose utilization due to chronic inflammation-induced insulin resistance. Insulin resistance is increasingly appreciated to affect non-canonical tissues, such as the brain, where it has been connected to age-associated inflammation and neurodegeneration. We will establish how the inflamed marrow milieu directly promotes insulin/IGF-1 pathway resistance, how this drives autophagy engagement and metabolic adaptation in a subset of old HSCs, and whether old HSC regenerative potential can be improved through fasting/refeeding interventions via normalization of insulin sensitivity and glucose uptake. In Aim 2, we will further dissect how replication stress contributes to the functional exhaustion of aged HSCs. In particular, we will focus on the fragile ribosomal DNA (rDNA) loci, which are severely impacted by replication stress in old HSCs, interfering with ribosome biogenesis. Defects in ribosome biogenesis lead to an accumulation of free ribosomal proteins triggering activation of a p53-dependent nucleolar stress response, as well as defects in protein translation, whose stringent regulation is critical for maintaining HSC functionality. We will explore the interplay between replication and nucleolar stress, investigate the intrinsic and extrinsic mechanisms surrounding decreased ribosomal biogenesis and impaired proteostasis, and identify the cellular programs responsible for the onset of replication stress in old HSCs to design functional rejuvenation interventions. This work has exciting implications for elucidating the biology of HSC aging at molecular resolution and identifying actionable targets for promoting HSC functional longevity, a logical strategy for restoring blood and immune cell production in the elderly.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
