The roles of primary cilia in cardiovascular system

描述(申请人提供)：多囊肾病(PKD)是一种全身性肾病，以进行性双侧肾囊肿形成为特征，导致肾功能逐渐下降。虽然它通常被归类为肾脏疾病，但大多数PKD患者死于心血管并发症，如高血压、动脉瘤、出血等。然而，很少有人关注这些并发症的基础科学方面。我们认为，PKD与机械感觉纤毛的遗传和功能缺陷有关，导致钙信号异常，从而导致心血管并发症。在这里，我们假设初级纤毛在内皮细胞的流体剪切感觉中起重要作用。利用PKD小鼠模型中的内皮细胞(如Tg737、PKD1和PKD2)，我们将研究PKD内皮细胞是否具有与先前在PKD上皮细胞一样的流体剪切传感的生物力学功能障碍。我们将进一步研究纤毛作为机械感官细胞器是否具有感知流体剪切力的独特生物物理能力。鉴于所有细胞都能够感知细胞外信号，我们打算问纤毛的机械感知有多具体。我们将使用一组不同的刺激来检查纤毛在流体剪切传感中的特异性。我们将比较流体剪切力、质膜扭曲和药物配体引起的细胞反应。我们将利用内皮细胞的生物物理(钙)和生化(一氧化氮)特性来研究它们在机械流体传感中的作用。因此，本提案旨在为PKD和非PKD患者中高血压等心血管疾病的发病机制提供新的见解。这项拟议的研究还将促进对纤毛生物学在与心血管生理学和病理生理学相关的体液传感方面的科学理解。尽管PKD经常被描述为最常见的人类遗传病之一，但与公共卫生相关；新的终末期肾病(ESRD)病例中只有4%属于囊性疾病类别。另一方面，高血压是ESRD的第二大常见原因，也是导致心血管死亡的主要原因之一。由于PKD中高血压的发病机制尚不清楚，本提案旨在了解高血压的分子病理，并提供信息，使更精确和特定的药物干预有可能有效地治疗或降低高血压。

DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a systemic nephropathy characterized by progressive bilateral renal cyst formation that results in a gradual decline in renal function. Although it is most commonly categorized as a kidney disease, the majority of patients with PKD die due to cardiovascular complications such as hypertension, aneurysm, hemorrhage, etc. Nonetheless, very little attention has been focused on the basic science aspects of these complications. We believe that PKD is associated with both genetic and functional defects in mechanosensory cilia, causing aberrant calcium signaling that lead to cardiovascular complications. Here, we hypothesize that primary cilia play an important role in fluid-shear sensing in endothelial cells. Using endothelial cells from Pkd mouse models (such as Tg737, Pkd1, and Pkd2), we will study whether Pkd endothelial cells have biomechanical dysfunction in fluid-shear sensing similar to those previously demonstrated in Pkd epithelial cells. We will further study whether cilia, acting as mechanical-sensory organelles, have unique biophysical abilities to sense fluid-shear stress. Given that all cells are capable of sensing extracellular signals, we intend to ask how specific is the mechanical sensing by cilia. We will use a set of different stimuli to examine the specificity of cilia in fluid-shear sensing. We will compare cellular responses induced by fluid-shear stress, plasma membrane distortion, and pharmacological ligands. We will use both biophysical (calcium) and biochemical (nitric oxide) properties of endothelial cells to study their involvement in mechanofluid sensing. Thus, the present proposal is positioned to provide new insights into mechanisms of cardiovascular diseases, such as hypertension, in both PKD and non-PKD patients. The proposed study will also advance scientific understanding of cilia biology in fluid sensing related to cardiovascular physiology and pathophysiology. PUBLIC HEALTH RELEVANCE Although PKD is often described as one of the most common human genetic diseases; only 4% of the cases of new end-stage renal disease (ESRD) have been in the cystic disease category. On the other hand, hypertension is the second most common cause of ESRD and is one of the leading causes of cardiovascular death. Because the pathogenesis of hypertension in PKD is still unknown, the present proposal is designed to understand the molecular pathology of hypertension and to offer information enabling more precise and specific pharmacological interventions with the potential to effectively treat or reduce high blood pressure.