Extrarenal Functions of Polycystin-1

Polycystin-1 的肾外功能

基本信息

批准号：
8097524
负责人：
L DARRYL QUARLES
金额：
$ 30.4万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097524
关键词：
Ablation Adipocytes Affect Anabolic Agents Area Autosomal Dominant Polycystic Kidney Back Binding Biological Process Biology Bone Development Bone Marrow Calcium Channel Cell surface Cells Cilia Code Complex Cystic Kidney Diseases Development Disease Epithelial Cells Genes Genetic Growth and Development function Homeostasis In Vitro Kidney Knockout Mice Knowledge Lead Ligands Link Mediating Mediator of activation protein Molecular Target Mus Mutation Osteoblasts Osteocytes Osteogenesis Osteopenia PKD1 gene PKD2 gene PKD2 protein Pathway interactions Play Process Proteins Role Signal Pathway Site Skeletal Development Skeletal bone Staging Tissues Translating bone bone mass cell growth cell type cilium biogenesis dentin matrix protein 1 design in vivo lipid biosynthesis novel osteoblast differentiation polycystic kidney disease 1 protein postnatal promoter public health relevance receptor skeletal skeletal abnormality skeletal dysplasia

项目摘要

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. PUBLIC HEALTH RELEVANCE: We have discovered that polycystins and primary cilia play important roles in skeletal development and postnatal bone function through mouse genetic studies that conditionally deleted Pkd1 and Kif3a from the osteoblast lineage in vivo. These findings suggest that the primary cilium/polycystin complex acts as a hub to sense environmental clues and translate them into multiple signaling pathways that sustain osteoblastic development and sustain the differentiated state of mature osteoblast, which lead to a net positive effect on bone mass; and as such, represent a new area of bone biology and an identification of a novel molecular target to design anabolic treatments for osteopenic disorders. In addition, a greater knowledge of polycystins and primary cilia functions in a different cellular context could translate into a broader understanding of their functions in the kidney.

描述（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），它们相互作用形成在许多组织和细胞类型中广泛表达的功能性多囊蛋白复合物。 PKD1 或 PKD2 基因的失活突变会导致常染色体显性多囊肾病 (ADPKD)。 ADPKD 的研究阐明了多囊蛋白的功能及其与肾上皮细胞初级纤毛的相互依赖性；然而，它们仅提供了有限的窗口来了解多囊蛋白/初级纤毛复合物在其他组织（例如骨）中潜在的更广泛功能。我们发现Pkd1和Pkd2以及初级纤毛存在于成骨细胞和骨细胞中，来自Pkd1缺失小鼠的初级成骨细胞在体外具有受损的成骨细胞分化能力和分化为脂肪细胞的倾向，并且有条件地删除Pkd1在小鼠成熟的成骨细胞中，由于成骨细胞介导的骨形成受损而导致骨质减少，这也与体内骨髓脂肪生成增加有关。这些发现表明多囊蛋白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蛋白的骨骼功能，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内不同阶段的Pkd1和Pkd2，包括前成骨细胞、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，我们将检查骨特异性删除 Kif3a 对破坏成骨细胞谱系中初级纤毛形成的影响。我们提出这样的假设：多囊蛋白的丢失导致前成骨细胞、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、分化程度较低的状态，并对大量的成骨细胞做出异常反应。影响出生后骨骼发育和骨形成的环境线索。总体而言，我们的研究将把多囊蛋白/初级纤毛复合物定义为骨中新的合成代谢途径，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，更多地了解多囊蛋白在骨骼中的具体功能将有助于阐明它们的整体功能，并将其转化回肾脏和其他组织。公共健康相关性：通过小鼠遗传学研究，我们发现多囊蛋白和初级纤毛在骨骼发育和出生后骨功能中发挥着重要作用，这些研究有条件地从体内成骨细胞谱系中删除了 Pkd1 和 Kif3a。这些发现表明，初级纤毛/多囊蛋白复合物充当感知环境线索的枢纽，并将其转化为多种信号通路，维持成骨细胞发育并维持成熟成骨细胞的分化状态，从而对骨量产生净积极影响；因此，代表了骨生物学的一个新领域，并确定了一个新的分子靶标，用于设计骨质减少疾病的合成代谢治疗方法。此外，对多囊蛋白和初级纤毛在不同细胞环境中功能的更多了解可以转化为对其在肾脏中的功能的更广泛的了解。