Immune Renal Injury

免疫性肾损伤

• 批准号: 6999097
• 负责人: MICHAEL R. VAUGHAN
• 金额: $ 5.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-12 至 2007-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999097
• 关键词: DNA damage; antibody; biological signal transduction; cell growth regulation; cell proliferation; cellular pathology; complement; diabetic nephropathy; gene expression; genetic regulation; genetically modified animals; glomerulonephritis; glomerulosclerosis; kidney disorder; kinase inhibitor; laboratory mouse; p53 gene /protein; podocyte; postdoctoral investigator; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Injury, to the terminally differentiated glomerular podocyte causes proteinuria in diabetic and non-diabetic renal disease. The inability of podocytes to proliferate adequately and replace those lost following injury underlies the decline in renal function due to glomerulosclerosis. In this grant proposal, we will test the central hypothesis that a novel mechanism limiting podocyte proliferation is DNA damage, with a focus on immune-mediated injury. Studies will be performed in cultured immortalized mouse podocytes, and in experimental models of podocyte injury in mice. In the first specific aim, we will show that DNA damage occurs in podocytes following sublytic C5b-9 (membrane attack complex) injury, and examine which signaling pathways mediate this effect. In the second aim, we will test the hypothesis that C5b-9 increases p53, which limits podocyte proliferation. In the final aim, we will test the hypothesis that the CDK-inhibitor, p21, regulates p53. The ultimate goal of this grant is to identify new targets for potential therapies in order to reduce the heavy burden of disease in patients with glomerular disease.

描述（由申请人提供）：损伤，肾小球足细胞会导致糖尿病和非糖尿病肾脏疾病引起蛋白尿。足细胞无法充分增殖并取代受伤后损失的人是由于肾小球硬化引起的肾功能下降的基础。在这项赠款建议中，我们将检验一个中心假设，即一种限制足细胞增殖的新机制是DNA损伤，重点是免疫介导的损伤。研究将在培养的永生小鼠足细胞和小鼠足细胞损伤的实验模型中进行。在第一个特定目的中，我们将表明，在Sublytic C5B-9（膜攻击复合物）损伤之后，DNA损伤发生在足细胞中，并检查哪种信号通路介导了这种效果。在第二个目标中，我们将检验以下假设：C5B-9增加了p53，这限制了足细胞增殖。在最终目标中，我们将检验以下假设：CDK抑制剂P21调节p53。该赠款的最终目标是确定潜在疗法的新靶标，以减轻肾小球疾病患者的疾病负担。