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Endothelial Cell in Progressive Renal Disease

进行性肾病中的内皮细胞

基本信息

批准号：
7919178
负责人：
Richard Joseph Johnson
金额：
$ 8.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-11 至 2010-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919178
关键词：
Acute Kidney Failure Address Age Binding Biology Birth Blood Pressure Blood Vessels Blood capillaries Cells Chronic Kidney Failure Clinical Collecting Cell Cyclosporine Cyclosporins Data Dependovirus Development Diabetes Mellitus Disease Documentation Duct (organ) structure Endothelial Cells Epithelial Epithelial Cells Functional disorder Future Gene Transfer Glomerular Capillary Growth Factor Overexpression Growth and Development function Health Hemolytic-Uremic Syndrome Histologic Human Hyperplasia Hyperuricemia Hypoxia In Vitro Infiltration Inflammation Injury Ischemia Kidney Kidney Diseases Kidney Failure Knock-out Knowledge Lead Limb structure Link Long-Term Effects Mediating Modeling Mus N,N-dimethylarginine Nitric Oxide Nitric Oxide Pathway Nitric Oxide Synthase Organ Outcome Pathway interactions Permeability Physiology Play Pre-Eclampsia Prevention Process Production Rattus Reaction Recovery Renal function Reporting Research Personnel Role Site Smooth Muscle Myocytes System Testing Thick Tubular formation UMOD gene Up-Regulation Urate Oxidase Uric Acid VEGFA gene Vascular Diseases Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors adeno-associated viral vector aquaporin-2 capillary chemokine cost human NOS3 protein human VEGF protein human disease improved inhibitor/antagonist insight kidney epithelial cell kidney vascular structure mature animal monocyte mouse Cre recombinase mutant novel overexpression podocyte receptor repaired research study response treatment planning

项目摘要

DESCRIPTION (provided by applicant): Renal failure is increasing at the rate of 6% with a cost of 16 billion dollars per year; thus developing new therapies for kidney disease is of paramount importance. In the previous renewal, we demonstrated that a loss of constitutive expression of vascular endothelial growth factor (VEGF) occurs in several models of renal disease, and that replacement with VEGF could slow progression via its ability to stimulate renal capillary repair. In this proposal we continue our studies of the physiology and pathophysiology of VEGF in renal disease. In Aim 1 we will test the hypothesis that the constitutive expression of VEGF in specific tubular cells (collecting ducts and medullary thick ascending limb cells) plays a critical trophic role for the renal (peritubular) capillaries in development and in the adult animal. This will be tested by selectively knocking out VEGF in these tubular cells using the Cre-loxP approach. In Aim 2 we will test the hypothesis that VEGF administration may not be beneficial when endothelial NO levels are low, and in fact may accelerate vascular disease via its effects on monocytes and vascular smooth muscle cells. This will be tested by examining the effect of long-term VEGF expression (by gene transfer using the AAV vector system) in renal diseases in which endogenous NO levels are reduced or maintained. In Aim 3 we will test the hypothesis that the specific VEGF receptors may govern whether VEGF stimulation is good or bad, in that stimulation of VEGFR-1 is expected to exacerbate renal vascular injury whereas stimulation of VEGFR-2 should accelerate capillary repair and renal recovery, independent of the status of the NO system. This will be tested by the overexpression of VEGF mutants specific for each receptor in renal diseases in the presence or absence of NO blockade. Documentation of the role of VEGF in the normal kidney, the importance of the NO system in mediating the responses to VEGF, and the specific role of each receptor in this process should provide the key information to help guide future studies for the use of VEGF as a novel treatment of kidney disease.

描述(申请人提供)：肾功能衰竭正在以每年160亿美元的速度增加，因此开发肾脏疾病的新疗法是至关重要的。在先前的更新中，我们证明了在几种肾脏疾病模型中发生了血管内皮生长因子(VEGF)结构性表达的丧失，并且用VEGF替代可以通过刺激肾脏毛细血管修复来减缓进展。在这项建议中，我们继续研究血管内皮生长因子在肾脏疾病中的生理学和病理生理学。在目标1中，我们将验证这样一种假设，即在特定的肾小管细胞(集合管和髓质厚的上肢细胞)中的结构性表达对发育中的肾(管周)毛细血管和成年动物起着关键的营养作用。这将通过使用Cre-loxP方法选择性地敲除这些肾小管细胞中的血管内皮生长因子来进行测试。在目标2中，我们将检验这样一种假设，即当内皮细胞NO水平较低时，给予血管内皮生长因子可能无益，实际上可能通过对单核细胞和血管平滑肌细胞的影响而加速血管疾病。这将通过检测内源性NO水平降低或维持的肾脏疾病中长期表达的血管内皮生长因子(通过使用AAV载体系统进行基因转移)的效果来检验。在目标3中，我们将检验一种假说，即特定的血管内皮生长因子受体可能决定血管内皮生长因子刺激的好坏，即血管内皮生长因子受体-1的刺激可能加重肾血管损伤，而血管内皮生长因子受体-2的刺激将加速毛细血管修复和肾脏恢复，而与NO系统的状态无关。这将通过肾脏疾病中每种受体特异性的血管内皮生长因子突变体在存在或不存在阻断的情况下过度表达来检验。关于血管内皮生长因子在正常肾脏中的作用，一氧化氮系统在介导对血管内皮生长因子的反应中的重要性，以及每个受体在这一过程中的具体作用的文献将提供关键信息，以帮助指导未来使用血管内皮生长因子作为肾脏疾病的新治疗方法的研究。

项目成果

期刊论文数量（89）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Abnormal angiogenesis in diabetic nephropathy.

DOI：
10.2337/db09-0119
发表时间：
2009-07
期刊：
Diabetes
影响因子：
7.7
作者：
Nakagawa T;Kosugi T;Haneda M;Rivard CJ;Long DA
通讯作者：
Long DA

A breakthrough in diabetic nephropathy: the role of endothelial dysfunction.

糖尿病肾病的突破：内皮功能障碍的作用。

DOI：
10.1093/ndt/gfm380
发表时间：
2007
期刊：
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
影响因子：
0
作者：
Nakagawa,Takahiko;Segal,Mark;Croker,Byron;Johnson,RichardJ
通讯作者：
Johnson,RichardJ

Hormonal and cytokine effects of uric acid.

尿酸的激素和细胞因子效应。

DOI：
10.1097/01.mnh.0000199010.33929.7f
发表时间：
2006
期刊：
Current opinion in nephrology and hypertension
影响因子：
3.2
作者：
Sánchez-Lozada,LauraG;Nakagawa,Takahiko;Kang,Duk-Hee;Feig,DanI;Franco,Martha;Johnson,RichardJ;Herrera-Acosta,Jaime
通讯作者：
Herrera-Acosta,Jaime

Could uric acid have a role in acute renal failure?