Dysregulated Angiogenesis in ADPKD

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）是最常见的危及生命的遗传性疾病，影响60万美国人和全球1250万人。ADPKD的特征是多发性肾囊肿的发展和生长，最终取代正常肾实质，导致肾功能最终丧失。此外，ADPKD患者中高血压的早期发作和左心室肥大的发生率增加与死亡风险增加相关。尽管在十多年前就发现了与ADPKD相关的致病基因，但影响肾囊肿生长的因素以及肾脏疾病的进展在很大程度上仍然未知。在ADPKD中的囊肿生长和良性肿瘤的生长之间存在相似性;即囊性肾上皮细胞的增殖增加和肾囊肿表面上发生的血管生成。在本提案中，我们试图描述ADPKD严重程度范围内与囊肿生长、肾损伤和心脏损伤相关的血管生成变化。我们提出了一种新的方法来研究膀胱生成，重点是人类的研究。因此，基于我们的初步数据，我们假设血管生成生长因子的异常表达在ADPKD发病机制的各个阶段都起作用。具体来说，我们认为促血管生成生长因子的局部上调表达刺激了肾囊肿的生长，表现为肾脏结构的变化。此外，血管生成生长因子的表达水平升高与通过左心室质量增加评估的心脏结构损伤相关。因此，本提案的具体目的是表征疾病进展不同阶段循环和尿液血管生成生长因子水平的变化及其与肾脏结构和功能以及心脏结构的关系。在更多的实验目的中，从具有基于肾脏体积的不同阶段的肾病严重程度的患者的尿液中回收的脱落的肾细胞将用于在mRNA和蛋白质水平上检查血管生成介质的表达。这些研究的结果将影响ADPKD未来的研究方向。特别是，拟议研究的积极结果应该为在ADPKD患者中进行大型、确定性、干预性研究的计划提供信息。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening genetic disease affecting 600,000 Americans and 12.5 million people worldwide. ADPKD is characterized by the development and growth of multiple renal cysts that eventually replace the normal renal parenchyma resulting in ultimate loss of renal function. Moreover, early onset of hypertension in ADPKD patients and increased incidence of left ventricular hypertrophy are associated with heightened mortality risk. Despite discovery of the causative genes associated with ADPKD more than a decade ago, the factors that affect the growth of renal cysts and hence the progression of renal disease remain largely unknown. There are similarities between cyst growth in ADPKD and growth of a benign tumor; namely increased proliferation of the cystic renal epithelial cells and angiogenesis occurring on the surface of renal cysts. In this proposal we seek to characterize the angiogenic changes associated with cyst growth, renal injury and cardiac damage across the spectrum of ADPKD severity. We propose a novel approach to the study of cystogenesis with focus on human studies. Accordingly, based on our preliminary data we hypothesize that that aberrant expression of angiogenic growth factors plays a role in all stages of the pathogenesis of ADPKD. Specifically, we propose that local up-regulated expression of pro-angiogenic growth factors stimulates renal cyst growth as manifest by changes in renal structure. In addition, elevated expression levels of angiogenic growth factors are associated with cardiac structural damage assessed by increase in left ventricular mass. Thus, the specific aims of this proposal are to characterize the changes in both circulating and urinary angiogenic growth factor levels at different stages of disease progression and their relationship with renal structure and function and cardiac structure. In a more experimental aim exfoliated renal cells recovered from urine of patients with different stages of renal disease severity based on kidney volume will be used to examine expression of angiogenic mediators at the mRNA and protein level. The results of these studies will impact future research directions in ADPKD. In particular, positive results of the proposed study should inform about the planning of a large, definitive, interventional study in patients with ADPKD.