Misregulation of receptor tyrosine kinase signaling in PKD

PKD 中受体酪氨酸激酶信号传导的失调

• 批准号: 8726973
• 负责人: Jordan A Kreidberg
• 金额: $ 35.52万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726973
• 关键词: Accounting; Affect; Apoptosis; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Basement membrane; Behavioral; Biochemical; Cell Polarity; Cell Proliferation; Cell membrane; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Cilia; Cyst; Development; Dialysis procedure; Disease; End stage renal failure; Epithelial; Epithelial Cells; Failure; Fluids and Secretions; Gene Expression; Genes; Golgi Apparatus; Graft Rejection; Grant; Health Care Costs; Hereditary Disease; High Prevalence; Individual; Integral Membrane Protein; Integrins; Kidney; Kidney Transplantation; Laboratories; Lead; Ligands; Molecular; Mutation; Outcome; PKD1 gene; PKD2 gene; Pathogenesis; Pattern; Pharmaceutical Preparations; Polycystic Kidney Diseases; Protein Glycosylation; Proto-Oncogene Protein c-met; Public Health; Publishing; Quality of life; Receptor Protein-Tyrosine Kinases; Renal dialysis; Renal function; Renal tubule structure; Research; Research Personnel; Role; Signal Transduction; Structure; Technology; Testing; Transplantation; Treatment Cost; Tubular formation; United States; Universities; Work; basolateral membrane; cost; glycosylation; impaired productivity; meetings; overexpression; prevent; response; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a hereditary disease with a high prevalence and without a cure. PKD is characterized by numerous cysts within the kidneys of afflicted individuals. The cysts formed in PKD can greatly enlarge the kidneys while replacing the normal kidney structures, resulting in reduced kidney function and progression to end-stage renal disease, that can only be treated by lifelong dialysis or kidney transplants. As a disease that affects 1 in 800~1000 individuals, PKD is among the most common genetic disorders. In the United States, there are 600,000 individuals, and worldwide 12.5 million, with PKD [1]. Thus, PKD represents a major public health issue, and accounts for hundreds of millions (and perhaps over a billion) of dollars in health care costs, particularly for dialysis treatments and the cost of drugs that prevent transplant rejections, as well as the cost involved of decreased productivity and impaired quality of life of individuals with PKD. For all these reasons, it is of great importance to discover treatments that directly affect the molecular causes of PKD, and that will prevent the progression to end-stage renal disease and dialysis or transplantation. The mechanism of cyst formation in PKD is unknown: There are both autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms of PKD. ADPKD is more common and is caused by mutations in either the PKD1 or PKD2 genes, that encode Polycystin1 or Polycystin2, respectively [2]. Despite an enormous amount of intensive study in many laboratories, the mechanism of cyst formation remains incompletely understood. Recent progress in PKD research suggests the following potential mechanisms that could lead to cyst formation: (1) increased cell proliferation and/or apoptosis within epithelial tubules of the kidney; (2) enhanced fluid secretion into tubular lumina; (3) abnormality in the interaction of epithelial cells with their underlying basement membrane (cell-matrix adhesion) or with each other (cell-cell adhesion); (4) alterations in epithelial cell polarity; and (5) abnormal ciliary function. In our previous work we demonstrated a role of 31 integrin is cell-cell adhesion, in addition to cell-matrix adhesion. We have also demonstrated that the receptor tyrosine kinase c-Met requires interaction with 31 integrin for maximal activation in response to its ligand, HGF. In extending this work to PKD, we have found that 31 integrin is not properly localized to the plasma membrane, and c-Met is over-expressed in Pkd1-/- cells. This appears to be due to a failure to ubiqutinate c-Met after stimulation with HGF. Failure to ubquitinate c-Met is due to sequestration of the E3 ubiquitin ligase c-Cbl by 31 integrin in the Golgi apparatus. This grant will investigate the roles of c-Cbl, c-Met and protein glycosylation in the pathogenesis of PKD.

描述（由申请人提供）：多囊性肾脏疾病（PKD）是一种遗传性疾病，患病率很高，无法治愈。 PKD的特征是受苦个体的肾脏中许多囊肿。 PKD中形成的囊肿可以大大扩大肾脏，同时更换正常的肾脏结构，从而导致肾功能降低并发展为终末期肾脏疾病，只能通过终身透析或肾脏移植剂来治疗。作为一种影响800至1000个人的疾病，PKD是最常见的遗传疾病之一。在美国，有60万个人，全球1,250万人，PKD [1]。因此，PKD代表了一个重大的公共卫生问题，占医疗保健成本（尤其是透析治疗以及防止移植拒绝的药物成本）的数亿（甚至超过十亿）的保健费用，以及降低生产力和PKD患者生活质量的成本。由于所有这些原因，发现直接影响PKD分子原因的治疗方法非常重要，这将防止发展为终末期肾脏疾病以及透析或移植。 PKD中囊肿形成的机制尚不清楚：PKD既有常染色体显性剂（ADPKD）和常染色体隐性（ARPKD）形式。 ADPKD更为常见，是由分别编码PolycyStin1或PolycyStin2的PKD1或PKD2基因突变引起的[2]。尽管在许多实验室中进行了大量深入研究，但囊肿形成的机制仍未完全理解。 PKD研究的最新进展表明，可能导致囊肿形成的以下潜在机制：（1）肾脏上皮小管内的细胞增殖和/或凋亡增加； （2）增强的流体分泌到管状腔； （3）上皮细胞与其基础基底膜的相互作用异常（细胞 - 矩阵粘附）或彼此（细胞细胞粘附）； （4）上皮细胞极性的改变； （5）异常睫状功能。 在我们以前的工作中，我们证明了31整联蛋白的作用是细胞 - 细胞粘附，除了细胞 - 基质粘附。我们还证明，受体酪氨酸激酶C-MET需要与31整合素相互作用，以应对其配体HGF的最大激活。在将这项工作扩展到PKD时，我们发现31整合素无法正确地定位于质膜，并且C-MET在PKD1 - / - 细胞中过表达。这似乎是由于用HGF刺激后未能进行ubiqutinate c-met。未能泛素C-MET是由于高尔基体中31整合素对E3泛素连接酶C-CBL的隔离造成的。该赠款将研究C-CBL，C-MET和蛋白质糖基化在PKD发病机理中的作用。

项目成果

Identification of novel glycans with disialylated structures in α3 integrin from mouse kidney cells with the phenotype of polycystic kidney disease.

鉴定来自具有多囊肾病表型的小鼠肾细胞的α3整合素中具有二唾液酸化结构的新型聚糖。

• DOI: 10.1021/pr5009702
• 发表时间: 2014
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Zhang,AnnaFan;Wu,Shiaw-Lin;Jung,Yunjoon;Qin,Shan;Hancock,WilliamS;Kreidberg,JordanA
• 通讯作者: Kreidberg,JordanA