Non-hypertensive cardiac disorders in polycystic kidney disease

 个人描述(申请人提供)：我的长期职业目标是作为一名独立的研究员，为肾脏和心脏相关领域做出贡献，这将带来更好的治疗方法 肾脏疾病。常染色体显性遗传性多囊肾病(ADPKD)是一种常见的遗传性疾病，由多囊蛋白1或多囊蛋白2(由PKD1或PKD2基因编码)突变引起。然而，ADPKD死亡的主要原因与心脏有关，但PKD1或PKD2的突变如何导致以及导致心脏症状的分子事件尚不清楚。值得注意的是，我们最近的数据显示，携带PKD2突变的人类患者中有9%患上特发性扩张型心肌病(IDCM)，而普通人群中IDCM的患病率为0.04%，比普通人低200倍。令人惊讶的是，这些患者中的大多数没有肾功能障碍或高血压。我在耶鲁大学我的导师芭芭拉·埃尔利希博士和共同导师劳伦斯·杨博士的指导下进行的研究扩展了这些初步研究。最近，我发现多囊蛋白2(PC2)含量减少的小鼠心脏功能得到改善。为了了解细胞内钙释放通道PC2如何影响心脏功能，我提出了三个目标，这将提供一个机会，在K99阶段进行训练，并在我独立的R00阶段实施特定的目标。在目标1中，我将研究PC2在基线和急性应激下对小鼠心脏功能的影响。在Ehrlich和Young博士的指导下，我将专门研究由于PC2的量而改变的钙依赖的收缩通路。在目标2中，我将探讨心肌肥厚与PC2之间的相互关系。90%以上的ADPKD患者存在心肌肥厚。令人兴奋的是，我的初步数据表明，在心肌肥厚期间，PC2的数量增加。为此，我将接受细胞信号和心肌肥厚领域的培训(与剑桥大学的H.L.Roderick博士和耶鲁大学的S.G.Campbell博士和K.A.Martin博士合作)。我建议将这一目标扩展到检查对人体组织的影响；这一部分将在R00阶段作为独立调查员完成。目标3将在R00阶段完成，我建议利用我将在目标1和2中学到的技术和技能，并将其应用于调查为什么带有PC2突变的ADPKD患者IDCM的发病率如此之高。完成这三个研究目标，以及我与导师Ehrlich博士和共同导师Young博士共同创建的培训和职业发展计划，将使我能够描述心脏中PC2依赖的通路，这将极大地提高对ADPKD心功能不全的了解。

 DESCRIPTION (provided by applicant): 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.