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Functional Characterization of WTX in Renal Development

WTX 在肾脏发育中的功能表征

基本信息

批准号：
7924889
负责人：
Miguel Nicolas Rivera
金额：
$ 13.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924889
关键词：
Accounting Adult Affect Award Biochemical Biological Models Cell Culture Techniques Cell Line Cell Proliferation Cells Childhood Childhood Renal Neoplasm Collaborations Defect Development Down-Regulation Embryo Epithelium Frasier Syndromes Genes Genitourinary system In Vitro Insulin-Like Growth Factor II Kidney Kidney Diseases Kidney Neoplasms Knockout Mice Knowledge Laboratories Lentivirus Vector Malignant Neoplasms Modeling Mus Mutation Nephroblastoma North America Organogenesis Pattern Phenotype Physiological Primary Neoplasm Property Proteins Public Health Applications Research Renal carcinoma Research Personnel Resolution Role Specimen TP53 gene Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation WT1 gene Wound Healing authority beta catenin comparative genomic hybridization kidney cell nephrogenesis novel podocyte programs research study tissue culture tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Wilms tumor is a pluripotent tumor which arises from embryonic renal precursors and is the most common pediatric kidney tumor and the fourth most common childhood malignancy. The first gene shown to be inactivated in Wilms tumor was the tumor suppressor WT1 and its functional characterization has emphasized the connection between these tumors and renal development. WT1 is essential for kidney development in mice and it is also responsible for genitourinary defects in the WAGR, Denys-Drash and Frasier syndromes. WT1, however, is inactivated in only 5-10% of sporadic Wilms' tumors. Alterations in beta-catenin, insulin-like growth factor 2 (IGF2) and p53 have been described but there are no known specific genetic defects that account for the majority of cases. The candidate for this KO8 award, Dr. Miguel Rivera, has identified and cloned a novel tumor suppressor gene, WTX, which is inactivated in 30% of sporadic Wilms tumor cases. Remarkably, WTX is expressed in a highly regulated pattern that partially overlaps WT1 during kidney development. Thus, by analogy to WT1, WTX is expected be a critical gene in both Wilms tumorigenesis and kidney development. The candidate now proposes to build on these initial results and characterize the functional properties of WTX in renal development. Aim 1: To characterize the biochemical properties of WTX. Lentiviral vectors will be used to express WTX at near physiologic levels and to determine associations with other proteins. Aim 2: To define the role of WTX in tissue culture models of renal development. The functional consequences of WTX upregulation and downregulation will be assessed in cell culture models of early renal development (RSTEM cells - a pluripotent renal cell line ) and fully differentiated kidney epithelia (a mouse podocyte cell line). Aim 3: To characterize the consequences of conditional WTX inactivation in the mouse kidney. A conditional WTX knockout mouse is being generated in collaboration with the laboratory of Dr. Nabeel Bardeesy. As part of this collaboration, the candidate will analyze the phenotype of this mouse in kidney development. It is anticipated that, by furthering our knowledge of early kidney development, this project will have public health applications in pediatric and adult kidney disease, kidney tissue repair and kidney cancer.

描述（由申请人提供）：