CELL BIOLOGY OF POLYCYSTIC KIDNEY DISEASE PROTEINS

多囊肾病（PKD）包括一系列遗传多样性疾病，其特征是发展为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。虽然常染色体显性形式的疾病主要影响成年人，但常染色体隐性形式通常影响儿童，发病率为20,000名新生儿中有1名。最近发现的常染色体隐性PKD突变基因PKHD1，使其基因产物“纤维囊蛋白”或“多导蛋白”（“FPC”）的研究首次成为可能。首席研究员之前对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产物（多囊毒素-1 （PC1）和-2 (PC2)）定位于肾上皮细胞的初级纤毛，并具有机械传感器的功能。来自首席调查员小组的初步数据

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.