The applicant hopes to establish an investigative program that links the dissection of molecular pathways of cardiomyocyte growth and survival with the development of surgical interventions for heart disease. The rich collaborative environment at UCSF and the support for active involvement in both cardiothoracic surgery and molecular research are expected to foster this goal. The current proposal would help form a basis for such a long term program by demonstrating the feasibility of analyzing cardiomyocyte signaling in the context of an experimental procedure for ischemic heart failure. Early generations of surgical interventions for heart failure, based on left ventricular (LV) geometry, have failed to account for complexities of myocardial biology, including apoptotic loss of cardiomyocytes and progressive thinning and fibrosis of the peri-infarct zone. Sphingosine-1-phosphate (S1P) has been associated both with cellular hypertrophy and with protection from apoptosis in cardiac myocytes. It is therefore hypothesized that a drop in S1P signaling accompanies infarct extension and cardiomyopathy after chronic LV infarction. It is further postulated that therapeutic cardiac remodeling (TCP) achieved via ventricular scar resection is associated with an increase in S1P signaling that leads to a reduction in cardiomyocyte apoptosis and an adaptive hypertrophic response in the remaining myocardium. To test these hypotheses, a mouse model of chronic coronary ligation will be used to analyze S1P receptor 1 (S1Pi) expression and responsiveness, as well as the activity and expression of sphingosine kinase 1 (SphK1), an enzyme that regulates the balance between pro-apoptotic ceramide and anti-apoptotic S1P. This activity will be correlated to cardiomyocyte apoptosis and to changes in LV structure and function. S1P signaling will then be studied in the context of ventricular scar resection, and correlated to changes in ventricular wall structure and function. Finally, pharmacologic stimulation of SphK1 and gene transfer of S1 P! And of SphK1 will test the feasibility of an intra-operative, molecular enhancement of surgical TCR.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Study Section
Special Emphasis Panel (ZHL1-CSR-B (O1))
Program Officer
Carlson, Drew E
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Yeh, Che-Chung; Fan, Yanying; Yang, Yi-Lin et al. (2017) Atrial ERK1/2 activation in the embryo leads to incomplete Septal closure: a novel mouse model of atrial Septal defect. J Biomed Sci 24:89
Fan, Yanying; Yang, Yi-Lin; Yeh, Che-Chung et al. (2017) Spacial and Temporal Patterns of Gene Expression After Cardiac MEK1 Gene Transfer Improve Post-Infarction Remodeling Without Inducing Global Hypertrophy. J Cell Biochem 118:775-784
Yeh, Che-Chung; Malhotra, Deepak; Yang, Yi-Lin et al. (2013) MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice. J Cell Biochem 114:47-55
Yeh, Che-Chung; Li, Hongzhe; Malhotra, Deepak et al. (2010) Distinctive ERK and p38 signaling in remote and infarcted myocardium during post-MI remodeling in the mouse. J Cell Biochem 109:1185-91
Wall, Samuel T; Yeh, Che-Chung; Tu, Richard Y K et al. (2010) Biomimetic matrices for myocardial stabilization and stem cell transplantation. J Biomed Mater Res A 95:1055-66
Yeh, Che-Chung; Malhotra, Deepak; Li, Hongzhe et al. (2009) Surgical ventricular reconstruction in mice: elucidating potential targets for combined molecular/surgical intervention. J Thorac Cardiovasc Surg 137:942-9
Li, Hongzhe; Malhotra, Deepak; Yeh, Che-chung et al. (2009) Myocardial survival signaling in response to stem cell transplantation. J Am Coll Surg 208:607-13
Yeh, Che-Chung; Li, Hongzhe; Malhotra, Deepak et al. (2009) Sphingolipid signaling and treatment during remodeling of the uninfarcted ventricular wall after myocardial infarction. Am J Physiol Heart Circ Physiol 296:H1193-9