Regulation of BMP Signaling in the Kidney

肾脏中 BMP 信号传导的调节

• 批准号: 7023865
• 负责人: HERBERT Y LIN
• 金额: $ 36.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023865
• 关键词: biological signal transduction; bone morphogenetic proteins; cell free system; gene deletion mutation; gene expression; glycosylphosphatidylinositols; growth factor receptors; immunofluorescence technique; laboratory rat; membrane proteins; protein binding; protein structure function; proteinuria; renal ischemia /hypoxia; tissue /cell culture; biological signal transduction; bone morphogenetic proteins; cell free system; gene deletion mutation; gene expression; glycosylphosphatidylinositols; growth factor receptors; immunofluorescence technique; laboratory rat; membrane proteins; protein binding; protein structure function; proteinuria; renal ischemia /hypoxia; tissue /cell culture

DESCRIPTION (provided by applicant): Acute renal failure (ARF) is an important cause of morbidity and mortality in hospitalized patients. Most ARF can be traced to ischemic injury due to a variety of etiologies. Unfortunately, no effective treatment strategies for ischemic renal injury exist, and thus the mortality rate of patients with severe ARF requiring dialysis has not decreased significantly over the last half century despite advances in supportive care. We have discovered a novel BMP signaling receptor, Dragon, whose expression in renal tubular cells is dynamically altered in ischemic renal injury. We propose to test the novel hypothesis that Dragon function will be important in the process of repair of the ischemic injured kidney. Knowledge we gain regarding the mechanism of action of Dragon and of the role of Dragon in the kidney would be of considerable importance in furthering our understanding of ischemic renal injury and ARF, and could be useful in eventual development of potential new diagnostic and treatment strategies. Bone Morphogenetic Proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) superfamily of growth factors that regulate many physiologic and pathophysiologic processes in the kidney including nephrogenesis, response to injury, and repair. Although their precise role in the adult kidney is not fully understood, BMPs appear to be protective against renal injury to a variety of insults including ischemia. We present Preliminary Studies that Dragon, a novel GPI-anchored protein which we have recently discovered, is highly expressed in the kidney in renal tubular epithelial cells and that its expression is dynamically altered during ischemic renal injury. Importantly, we demonstrate that 1) Dragon can augment signaling via the BMP pathway, 2) Dragon can bind to specific BMPs, 3) Dragon signals via the BMP type IB receptor, ALK6, and 4) Dragon signals via the R-Smad, Smad1. We propose to investigate further the molecular and cellular mechanisms of Dragon-mediated signaling via the BMP pathway in kidney cells and to study in detail Dragon expression and its consequences in the kidney during ischemic injury and repair.

描述（由申请人提供）：急性肾衰竭（ARF）是住院患者发病率和死亡率的重要原因。由于各种病因，大多数ARF可以追溯到缺血性损伤。不幸的是，没有有效的缺血性肾脏损伤的有效治疗策略，因此，尽管支持护理的进步，但在过去半个世纪中，需要透析的严重ARF患者的死亡率并未显着下降。我们发现了一种新型的BMP信号受体Dragon，其在肾小管细胞中的表达在缺血性肾损伤中动态改变。我们建议检验新的假设，即龙功能在修复缺血性损伤肾脏的过程中至关重要。关于龙的作用机理和龙在肾脏中的作用机制，我们获得的知识对于进一步的理解是对缺血性肾脏损伤和ARF的重要性，并且对于最终发展潜在的新诊断和治疗策略而言可能是有用的。骨形态发生蛋白（BMP）是生长因子的转化生长因子β（TGF-β）的成员，这些生长因子是调节肾脏中许多生理和病理生理过程的生长因子的成员。尽管尚未完全了解它们在成年肾脏中的精确作用，但BMP似乎可以防止肾脏受伤，包括包括缺血在内的各种侮辱。我们提出了初步研究，即我们最近发现的一种新型的GPI锚定蛋白，在肾小管上皮细胞的肾脏中高度表达，其表达在缺血性肾脏损伤过程中动态改变。重要的是，我们证明1）龙可以通过BMP途径增强信号，2）龙可以与特定的BMP结合，3）通过BMP类型IB受体，ALK6和4）通过R-SMAD，SMAD1的龙信号。我们建议通过肾细胞中的BMP途径进一步研究龙介导的信号传导的分子和细胞机制，并详细研究龙的表达及其在缺血性损伤和修复期间在肾脏中的后果。