My long-term career goal is to contribute to kidney and cardiac-related fields as an independent investigator that will lead to better ways of treating kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder, caused by mutations to either polycsytin 1 or polycystin 2 (encoded by genes pkd1 or pkd2). However, the main cause of mortality in ADPKD is cardiac related, but how mutations in pkd1 or pkd2 lead to and the molecular events that result in cardiac symptoms are not understood. Remarkably, our recent data show of 9% human patients with pkd2 mutations develop idiopathic dilated cardiomyopathy (IDCM), whereas the prevalence of IDCM in the general population is 0.04%, two hundred-fold lower. Strikingly, the majority of these patients do not have renal dysfunction, or hypertension. My studies under my Mentor, Dr. Barbara Ehrlich and Co-Mentor Dr. Lawrence Young at Yale University have extended these initial studies. Recently, I have determined that mice with decreased amounts of polycystin 2 protein (PC2) have improved cardiac function. To understand how PC2, an intracellular calcium release channel impacts cardiac function, I propose three Aims that will provide an opportunity to train, during the K99 phase, and to implement specific goals in my independent R00 phase.
In Aim 1, I will investigate how the amount of PC2 impacts cardiac function in mice under baseline and acute stress. I will be specifically look at calcium- dependent contractile pathways that are changed due to the amount of PC2, under the mentorship of Drs. Ehrlich and Young.
In Aim 2, I will investigate the interrelationship between cardiac hypertrophy and PC2. Over 90% of ADPKD patients have cardiac hypertrophy. Excitingly, my preliminary data indicates that the amount of PC2 increases during cardiac hypertrophy. In this Aim, I will gain training in the area of cellar signaling and cardiac hypertrophy (with collaborators Dr. H. L. Roderick, Cambridge University, and Drs. S. G Campbell and K. A. Martin, Yale University). I propose to extend this Aim to examine the effects in human tissue; this section will be completed as an Independent Investigator during the R00 phase.
Aim 3 will be completed during the R00 phase, and I propose to utilize the techniques and skills I will learn in Aims 1 and 2, and apply them to investigate why the incidence of IDCM is so high in ADPKD patients with mutations of PC2. Completion of these three research Aims, and the training and career development plan that I have created with my Mentor Dr. Ehrlich and Co-Mentor Dr. Young will enable me to describe PC2-dependent pathways in the heart that will dramatically improve the understanding into cardiac dysfunction in ADPKD.
Cardiac disorders are the main cause of mortality in the common genetic disorder polycystic kidney disease. The goal of this research is to understand how altered levels and mutations to polycystin 2 cause cardiac disorders. The findings from this study will greatly benefit the treatment of polycystic kidney disease patients.
| Giehl, Esther; Lemos, Fernanda O; Huang, Yan et al. (2017) Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch 469:1507-1517 |
| Padovano, Valeria; Kuo, Ivana Y; Stavola, Lindsey K et al. (2017) The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Mol Biol Cell 28:261-269 |
