Extrarenal Functions of Polycystin-1
Polycystin-1 的肾外功能
基本信息
- 批准号:8097524
- 负责人:
- 金额:$ 30.4万
- 依托单位:
- 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:
- 关键词:AblationAdipocytesAffectAnabolic AgentsAreaAutosomal Dominant Polycystic KidneyBackBindingBiological ProcessBiologyBone DevelopmentBone MarrowCalcium ChannelCell surfaceCellsCiliaCodeComplexCystic Kidney DiseasesDevelopmentDiseaseEpithelial CellsGenesGeneticGrowth and Development functionHomeostasisIn VitroKidneyKnockout MiceKnowledgeLeadLigandsLinkMediatingMediator of activation proteinMolecular TargetMusMutationOsteoblastsOsteocytesOsteogenesisOsteopeniaPKD1 genePKD2 genePKD2 proteinPathway interactionsPlayProcessProteinsRoleSignal PathwaySiteSkeletal DevelopmentSkeletal boneStagingTissuesTranslatingbonebone masscell growthcell typecilium biogenesisdentin matrix protein 1designin vivolipid biosynthesisnovelosteoblast differentiationpolycystic kidney disease 1 proteinpostnatalpromoterpublic health relevancereceptorskeletalskeletal abnormalityskeletal 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(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PC2,它们相互作用以形成功能性多囊蛋白复合物,在许多组织和细胞类型中广泛表达。 PKD1或PKD2基因的灭活突变引起常染色体显性多囊肾脏疾病(ADPKD)。 ADPKD的研究阐明了多囊素的功能及其对肾上皮细胞中原发性纤毛的相互依赖性。但是,它们仅提供了一个有限的窗口,即在其他组织(例如骨骼)中多囊这素/原发性纤毛络合物的潜在广泛功能。 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在骨质骨细胞介导的骨形成引起的骨质减少症中,这也与体内骨髓脂肪形成增加有关。这些发现表明,多囊素和原发性纤毛在骨骼中具有重要的生物学功能。为了进一步检查多囊的骨骼功能,我们将使用成骨细胞 - linege特定启动子-CRE小鼠从成骨细胞谱系内的不同阶段选择性地删除PKD1和PKD2,包括骨细胞前的骨细胞前,成熟的成骨细胞和骨细胞。为了探索骨中多囊和原发性纤毛的潜在相互依赖性,我们将研究KIF3A骨特异性缺失对破坏成骨细胞谱系中原发性纤毛形成的影响。 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.总体而言,我们的研究将将多囊/原发性纤毛复合物定义为骨骼中的新合成代谢途径,并可能为开发合成代谢剂治疗骨质疏松性疾病提供了新的靶标。此外,对骨骼中多囊蛋白的特定功能的更多知识将有助于阐明它们的整体功能,从而将其转化为肾脏和其他组织。
公共卫生相关性:我们已经发现,多囊菌素和原发性纤毛通过小鼠遗传研究在骨骼发育和产后骨功能中起着重要作用,这些研究从体内从成骨细胞谱系中有条件地删除了PKD1和KIF3A。这些发现表明,主要的纤毛/多囊蛋白络合物充当感知环境线索并将其转化为多种信号通路,以维持成骨细胞发展并维持成熟成骨细胞的差异化状态,从而导致对骨骼质量的净积极影响;因此,代表了骨生物学的新领域,并鉴定出一种新型分子靶标,以设计骨质减少性疾病的合成代谢处理。此外,在不同的细胞环境中,多囊素和原发性纤毛功能的知识更大,可以转化为对它们在肾脏中功能的更广泛的理解。
项目成果
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L DARRYL QUARLES其他文献
L DARRYL QUARLES的其他文献
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