Extrarenal Functions of Polycystin-1

描述（由申请人提供）：Pkd1编码PC1，一种跨膜受体样蛋白，Pkd2编码PC2，一种钙通道，两者相互作用形成功能性多囊蛋白复合物，广泛表达于许多组织和细胞类型中。PKD1或PKD2基因失活突变导致常染色体显性多囊肾病（ADPKD）。ADPKD的研究已经阐明了多囊毒素在肾上皮细胞中的功能及其对原代纤毛的依赖性；然而，他们只提供了一个有限的窗口，了解多囊毒素/初级纤毛复合物在其他组织（如骨）中潜在的更广泛的功能。我们发现，Pkd1和Pkd2以及原代纤毛存在于成骨细胞和骨细胞中，来自Pkd1缺失小鼠的原代成骨细胞在体外具有成骨细胞分化能力受损和向脂肪细胞分化的倾向，并且在小鼠成熟成骨细胞中有条件地缺失Pkd1导致成骨细胞减少，这是由于成骨细胞介导的骨形成受损，这也与体内骨髓脂肪生成增加有关。这些发现提示多囊毒素和初级纤毛在骨中具有重要的生物学功能。为了进一步研究多囊素的骨骼功能，我们将使用成骨细胞谱系特异性启动子cre小鼠选择性地删除成骨细胞谱系中不同阶段的Pkd1和Pkd2，包括成骨前细胞、成熟成骨细胞和骨细胞。为了探索骨中多囊蛋白和初级纤毛的潜在相互依赖性，我们将研究骨特异性缺失Kif3a对成骨细胞谱系中初级纤毛形成的影响。我们提出的假设是，多囊素的缺失导致前成骨细胞、成熟成骨细胞和骨细胞无法维持其分化和存活阶段，导致细胞恢复到增殖、低分化状态，并对影响骨骼发育和骨形成的众多环境线索做出异常反应。总之，我们的研究将确定多囊蛋白/初级纤毛复合体作为骨合成代谢的新途径，并可能为开发合成代谢药物治疗骨质疏松症提供新的靶点。此外，对骨骼中多囊素的特定功能的更多了解将有助于阐明它们的整体功能，这些功能将转化为肾脏和其他组织。

DESCRIPTION (provided by applicant): Pkd1 encodes PC1, a transmembrane receptor-like protein, and Pkd2 encodes PC2, a calcium channel, which interact to form functional polycystin complexes that are widely expressed in many tissues and cell types. Inactivating mutations of PKD1 or PKD2 genes cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). Studies of ADPKD have elucidated the functions of polycystins and their interdependence on primary cilia in renal epithelial cells; however, they have provided only a limited window into the potential broader functions of polycystins/primary cilia complexes in other tissues, such as bone. We have found that Pkd1 and Pkd2, as well as primary cilia are present in osteoblasts and osteocytes, that primary osteoblasts derived from Pkd1 null mice have impaired osteoblast differentiation capacity and a propensity to differentiate in to adipocytes in vitro, and that conditional deletion of Pkd1 in mature osteoblasts of mice results in osteopenia due to impaired osteoblast-mediated bone formation that is also associated with increased bone marrow adipogenesis in vivo. These findings suggest that polycystins and primary cilia have important biological function in bone. To further examine the skeletal functions of polycystins, we will use osteoblast-lineage specific promoter-Cre mice to selectively delete Pkd1 and Pkd2 from different stages within the osteoblastic lineage, including pre-osteoblasts, mature osteoblasts and osteocytes. To explore potential interdependence of polycystin and primary cilia in bone, we will examine the effect of bone-specific deletion of Kif3a to disrupt primary cilia formation in the osteoblastic lineage. We propose the hypothesis that the loss of polycystins results in the inability of pre-osteoblasts, mature osteoblasts, and osteocytes to maintain their stage of differentiation and survival, resulting in cells reverting to a proliferative, less differentiated state and responding abnormally to the multitude of environmental clues affecting skeletal development and bone formation postnatally. Overall, our studies will define the polycystin/primary cilium complex as a new anabolic pathway in bone as well as possibly provide a new target for developing anabolic agents to treat osteoporotic disorders. In addition, a greater knowledge of specific functions of polycystins in bone will help clarify their overall functions that will translate back to the kidney and other tissues.