CELL BIOLOGY OF POLYCYSTIC KIDNEY DISEASE PROTEINS

多囊肾疾病(‘PKD’)包括一系列遗传多样性疾病，其特征是发展成多个充满液体的肾囊肿并进展为肾功能衰竭。我们的长期目标是了解囊肿形成的分子机制，并为PKD患者开发合理的治疗方法。虽然常染色体显性遗传形式主要影响成年人，但常染色体隐性形式通常影响儿童，新生儿发病率为每20,000人中就有1人。最近发现的常染色体隐性遗传性PKD突变基因PKHD1的发现，使得对其基因产物--纤维囊藻蛋白或多聚体蛋白(FPC)的研究成为可能。首席调查员以前对PKD的主要形式进行了广泛的研究，并表明这种形式的基因突变的产物(多囊蛋白-1(PC1)和-2(PC2))定位于肾上皮细胞的初级纤毛中，并作为机械传感器发挥作用。首席调查员小组的初步数据 结果表明，FPC定位于犬肾上皮细胞纤毛，集中在基底体/中心体区域，并可能通过与多囊蛋白复合体的相互作用而介导机械感觉。在这项提案中，首席研究员计划定义FPC/多囊蛋白复合体，并验证FPC有助于肾上皮细胞机械感觉的假设。通过结合特定的细胞分析，她还建议研究FPC在细胞周期中的作用，并确定FPC功能的亚细胞位置。这些研究将可能揭示常染色体隐性PKD蛋白和常染色体显性PKD蛋白之间的功能关系，并将为疾病机制提供新的见解，可能导致新的治疗策略。

The polycystic kidney diseases ('PKD') comprise a range of genetically diverse disorders characterized by the development of multiple fluid-filled kidney cysts and progression to renal failure. Our long-term goal is to understand the molecular mechanisms underlying cyst formation and to develop rational therapies for PKD patients. While the autosomal dominant forms of the disease affect mostly adults, the autosomal recessive form typically affects children and has an incidence of 1 in 20,000 newborns. Recent Identification of PKHD1, the gene mutated in autosomal recessive PKD, has made the study of its gene product - 'fibrocystin' or 'polyductin' ('FPC') - possible for the first time. The Principal Investigator has previously worked extensively on the dominant forms of PKD and has shown that the products of the genes mutated in this form (polycystins -1 (PC1) and -2 (PC2)) are localized in the primary cilia of renal epithelial cells and function as mechanosensors. Preliminary data from the Principal Investigator's group reveal that FPC is localized to the cilium of canine kidney epithelial cells with concentration in the basal body/centrosome area and appears to mediate mechanosensation through interactions with polycystin protein complex. In this proposal, the Principal Investigator plans to define the FPC/polycystin protein complex and validate the hypothesis that FPC contributes to mechanosensation in renal epithelia. By using a combination of specific cellular assays, she also proposes to study the role of FPC in cell cycle, and to determine the subcellular locations of FPC function. The studies will likely reveal the functional relationship between the autosomal recessive PKD protein and the autosomal dominant PKD proteins, and will provide new insights into disease mechanisms which will likely lead to new strategies for therapy.