Non-motile primary cilia are organelles found on most cells where they play vital sensory and signaling roles required for normal human development and normal organ function. Defects in cilia assembly or function can lead to multiple human pathologies, called ciliopathies, including developmental defects, polycystic kidney disease, primary ciliary dyskinesia and several other syndromes. The focus of the proposed studies is on cardiomyocyte primary cilia. Although primary cilia have been observed in myocytes for over 40 years, there is currently little information about the roles of cilia in the heart. The new and surprising data show that sensory polycystin modulates L-type calcium channel (CaV1.2) to myocyte cilia. The polycystin and CaV1.2 complex plays an essential role in maintaining proper heart calcium and contractility in the heart. In Aim 1, molecular interaction between CaV1.2 and polycystin-2 in cardiomyocytes will be studied. The interaction and localization of CaV1.2 and polycystin-2 in primary culture of cardiomyocytes will be examined. More precise interacting domains of CaV1.2 and polycystin-2 will be delineated, in addition to mapping their subcellular localization in vivo. In Aim 2, the role of primary cilia in cardiomyocytes and hearts will be studied using cardiac specific mouse models without cilia mechanosensory function (Pkd2) or with abnormal cilia structure (Tg737). The cardiac phenotypes by the abnormal cardiac cilia under normal physiologic and pathologic conditions will be characterized. Pressure-overload induced-cardiac hypertrophy and heart failure models will be used to understand roles of primary cilia on cardiac output, cardiac systolic functions and diastolic functions, and cardiac remodeling (hypertrophy and fibrosis). In Aim 3, the mechanism involved in ciliary CaV1.2 in myocyte contraction will be studied. Calcium signaling, myocyte contractility and hypertrophy induced by CaV1.2 in the primary cilia vs. T-tubule will be differentiated. Of note is that it is currently believed that CaV1.2 localizes and functions only in plasma membrane invaginations T-tubule and caveolae. Overall, the proposed studies will provide novel information on physiology of CaV1.2 and the first analysis on the roles of primary cilia in the cardiomyocyte and heart function.
|Program type||Scientist Development Grant|
|Effective start/end date||07/01/2016 → 06/30/2019|