Dr. Wang had studied/worked in biomedicine for 14 yrs in Wuhan, China. He was appointed Assistant Professor in 2001, promoted to Associate Professor in 2005, tenured in 2006, and became full Professor and Director of the MD/PhD program in 2006. Basic biomedical sciences: biochemistry and molecular biology, anatomy, histology and physiology, cell biology and transgenics. Dr. X-J Wang's research laboratory is primarily funded by NIH R01 grants and focuses on protein quality control and degrada on in cardiovascular physiology and pathophysiology, molecular mechanisms of the progression from primary heart diseases to conges ve heart failure, and molecular pathogenesis of misfolded proteins.

 

Targeted removal of damaged/misfolded proteins in the cell is primarily performed by the ubiqui nproteasome system (UPS). When escaped from UPSmediated degrada on, misfolded proteins tend to form aberrant aggregates which are no longer accessible by the proteasome and are generally believed to be removed by macroautophagy. Remarkable accumula on of myocardial ubiqui nated proteins and autophagosomes are observed in human heart failure of nearly all causes, indica ve of UPS and autophagic dysfunc on in the development of cardiac failure. The crea on of stable cell lines, adenoviruses, and stable transgenic mice expressing a surrogate UPS substrate, such as green fl uorescence protein (GFP) modifi ed by fusion with degron CL1 (known as GFPu or GFPdgn), has made it possible and convenient to monitor dynamic changes in UPS performance in situ or in vivo, and thereby enabled my lab to demonstrate for the fi rst  me in intact animals that increases in misfolded proteins and resultant aberrant protein aggrega on impair UPS func on and cause proteasome func onal insuffi  ciency (PFI). Similarly, we and collaborators detected cardiac UPS func onal insuffi  ciency in acute ischemia/reperfusion (I/R), chronic pressure overload, and diabe c cardiomyopathy. Using both gain- and loss-of-func on approaches, we were able to demonstrate that PFI is a major factor underlying UPS malfunc on and plays an important pathogenic role in heart disease with 

increased proteotoxic stress such as proteinopathy, I/R injury and diabe c cardiomyopathy in mice. Furthermore, we have discovered that cGMP-dependent kinase (PKG) posi vely regulates the proteasome in cardiomyocytes, PKG ac va on by either gene c or pharmacological means, such as phosphodiesterase 5 (PDE5) inhibi on, promotes proteasome-dependent degrada on of a surrogate and a bona fi de misfolded protein in cardiomyocytes, and PDE5 inhibi on by sildenafi l reduces misfolded protein abundance and aggrega on and slows down disease progression in a well-established mouse model of cardiac proteinopathy. We have also collected strong evidence that the protec on of PDE5 inhibi on against I/R injury depends largely on improving proteasome func on. Muscarinic receptor ac va on can enhance cardiac proteasomal func on in a PKG dependent manner. These fi ndings demonstrate the feasibility to use pharmacological method to enhance UPSmediated degrada on of misfolded proteins and thereby to treat heart disease with elevated misfolded proteins. A good body of evidence has also demonstrated that increasing autophagy is benefi cial to the treatment of most heart diseases. Hence, improving cardiac protein quality control through UPS enhancement and increasing autophagic fl ux has emerged as a promising novel therapeu c strategy warranted for transla onal studies.