Incidence of heart failure is increased by 70-fold in populations >65 years old, constituting one of the leading causes of mortality in the US. The underlying mechanism is not clearly known but is postulated to involve chronic stress triggered pathological remodeling. p38 MARK is a critical pathway in cellular response to stresses and is altered in the failing heart. Loss of p38-[alpha] led to cardiac hypertrophy and decreased longevity in mice. Therefore, understanding the molecular mechanisms of p38 regulation and its downstream signaling in the heart can shed important insights into the disease mechanism. In preliminary studies, I have employed a proteomics approach to determine the molecular components of cardiac p38-[alpha] signaling complex. From these studies, I have found a novel interaction between p38- [alpha] and heat shock protein 90 (Hsp90) as well as its co-chaperone, Cdc37. p38 was shown to bind Cdc37 directly in vitro and inhibition of Hsp90 activity led to a rapid activation of p38. Prolonged HSP90 inhibition also resulted in cell death in a p38 dependent manner. These data point to a novel regulation of p38 activity through Hsp90/Cdc37 chaperone complex in cardiac myocyte death and survival. My preliminary study suggests a novel hypothesis that HSP90/Cdc37 is part of p38 signal complex in the heart via direct interaction and helps to maintain a low level of p38 activity at a basal state. Release of p38 from HSP90/Cdc37 complex leads to rapid activation via autophosphorylation and contributes to cell death under stress. In this proposal, I plan to test this hypothesis by accomplishing the following experiments:
Aim 1 : To determining the molecular basis of HSP90/Cdc37 interaction with p38 by mapping their interaction domains and characterizing its impact on p38 regulation.
Aim 2 : To reveal the molecular mechanism underlying Hsp90/Cdc37 mediated regulation of p38 activity via autophosphorylation.
Aim 3 : To examine the functional impact of Hsp90/Cdc37 mediated p38 regulation in the intact heart. From these studies, I will receive comprehensive training in a wide range of experimental tools and model systems. The results will contribute to a better understanding of signal regulation and transduction in the aging heart and potentially lead to more effective therapeutics for heart failure. ? ? ?
| Ota, Asuka; Wang, Yibin (2012) Cdc37/Hsp90 protein-mediated regulation of IRE1? protein activity in endoplasmic reticulum stress response and insulin synthesis in INS-1 cells. J Biol Chem 287:6266-74 |
| Ota, Asuka; Zhang, Jun; Ping, Peipei et al. (2010) Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte. Circ Res 106:1404-12 |
