Pathophysiology of Early Chronic Kidney Disease: Response to Ischemia-Reperfusion

早期慢性肾脏病的病理生理学：对缺血再灌注的反应

基本信息

批准号：
8697045
负责人：
Prabhleen Singh
金额：
$ 15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This is a 5-year proposal for the development of the candidate as a physician scientist in the arena of renal physiology and pathophysiology. It will allow an extended period of research training in basic physiologic methods to accomplish this goal. The mentor, Dr. Blantz, is a well-recognized leader in the field of renal physiology and has mentored numerous trainees to achieve successful academic careers. UCSD provides an ideal fostering environment for young investigators with opportunities to interact and collaborate with many well-established investigators within and outside the Division of Nephrology. In chronic kidney disease (CKD), adaptations in remaining nephrons help maintain the primary functions of the kidney i.e. filtration and salt balance in the earlier stages. In the face of successive nephron loss, the kidney has pre-defined and limited sets of physical factors (glomerular and tubular) that can be altered to maintain GFR. In addition a change in the pre-existing environment can influence the response to subsequent injury. A relative resistance to decline in GFR has been observed by us after an ischemic event in early subtotal nephrectomy (STN) in rat, a model of CKD. Our investigations of the physiologic, metabolic and molecular milieu in early STN provide valuable insights into the overall response of the kidney to injury. At baseline, adaptations in nephron function include an absence of tubuloglomerular feedback (TGF) response, which can curtail the decline in GFR seen normally. Other glomerular and tubular factors, yet unexamined, could also be important. Finally in vivo preconditioing can afford resistance to proximal tubuar cells. Using micropuncture and molecular biology techniques we propose to provide useful mechanistic information. The specific aims include: 1) Determine the degree to which the relative insensitivity of GFR to IR in the early stage is due to differences in TGF, physical factors, and other humoral factors using a simple, yet inclusive, network construct applied to micropuncture data. 2) Determine the underlying mechanisms of cellular resistance to ischemia in STN and the role of hypoxia inducible factor and its downstream effects in this response. These will be the first detailed analysis of the mechanisms of acute kidney injury in the presence of CKD.

描述（由申请人提供）：这是一项为期5年的提议，是在肾脏生理学和病理生理学领域担任医师科学家的候选人的一项提议。这将允许长期进行基本生理方法的研究培训，以实现这一目标。这位导师布兰茨博士是肾脏生理学领域的公认领导者，并指导了许多学员，以实现成功的学术职业。 UCSD为年轻的研究人员提供了理想的培养环境，并有机会与肾脏科内外的许多成熟的研究人员进行互动和合作。在慢性肾脏疾病（CKD）中，剩余的肾脏的适应有助于维持肾脏的主要功能，即较早阶段的过滤和盐平衡。面对连续的肾单位损失，肾脏具有预定且有限的物理因素集（肾小球和管状）以维持GFR。另外，现有环境的变化可能会影响对随后伤害的反应。在大鼠次体肾切除术（STN）中，我们观察到了GFR的相对抗药性，这是CKD模型的大鼠。我们对早期STN生理，代谢和分子环境的研究为肾脏对损伤的整体反应提供了宝贵的见解。在基线时，肾单位功能的适应性包括没有微关球反馈（TGF）反应，这可以减少正常观察的GFR下降。其他肾小球和管状因子（但未审查）也可能很重要。最终，体内前介质可以提供对近端大小细胞的抗性。使用微络合和分子生物学技术，我们建议提供有用的机械信息。具体目的包括：1）确定GFR在早期阶段对IR的相对不敏感性的程度是由于TGF，物理因素和其他适用于微功能数据的网络结构的差异，物理因素和其他体液因素的差异。 2）确定细胞对缺血性缺血性的潜在机制以及缺氧诱导因子的作用及其在此反应中的下游效应。这些将是对CKD存在的急性肾损伤机制的首次详细分析。