Advancing age is a major independent risk factor for cardiovascular disease. The prevalence of specific cardiovascular conditions such as cardiac hypertrophy/failure, atherosclerosis, and inflammation increase with age. Previous studies by the applicant's laboratory illuminated essential roles for KLFs in control of immunity, metabolism, and impact on the cardiovascular system. Nascent observations by the applicant build on the published corpus of work and identify KLFs as a heretofore unappreciated molecular control locus governing both lifespan and healthspan across metazoan life. The current application seeks to (a) determine which mammalian KLFs are linked to aging, (b) determine the effect of manipulating KLF4 on cardiac and vascular healthspan in aging mammals, and (c) determine the effect of manipulating myeloid KLF2 on aging/age-associated inflammatory states. Completion of the outlined work will provide fundamental insights with therapeutic implications regarding aging and age-associated cardiovascular disease.
The prevalence of specific cardiovascular conditions such as cardiac hypertrophy/failure, atherosclerosis, and inflammation increase with age. Recent studies by the applicant have identified a family of factors that control lifespan and healthspan from C. elegans to mammals. The current proposal seeks to fully define the role of KLF in aging and age-associated cardiovascular disease.
|Hsu, Kuo-Sheng; Zhao, Xuan; Cheng, Xiwen et al. (2017) Dual regulation of Stat1 and Stat3 by the tumor suppressor protein PML contributes to interferon ?-mediated inhibition of angiogenesis. J Biol Chem 292:10048-10060|
|Hsieh, Paishiun N; Zhou, Guangjin; Yuan, Yiyuan et al. (2017) A conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction. Nat Commun 8:914|