Hypertensive Renal Injury

高血压肾损伤

• 批准号: 7938592
• 负责人: PETER A DORIS
• 金额: $ 35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938592
• 关键词: Alleles; American; Animal Model; Breeding; Cardiovascular Diseases; Chromosome Mapping; Chronic; Congenic Strain; Control Locus; DNA Resequencing; Diabetes Mellitus; Dialysis procedure; Disease; Dyslipidemias; End stage renal failure; Generations; Genes; Genetic Predisposition to Disease; Genetic Variation; Heredity; Hypertension; Inbred SHR Rats; Individual; Injury; Insulin Resistance; Kidney; Kidney Diseases; Kidney Transplantation; Maps; Modeling; Oxidation-Reduction; Pathway interactions; Patients; Play; Population; Predisposition; Rattus; Relative (related person); Renal dialysis; Resistance; Resolution; Risk; Role; Single Nucleotide Polymorphism; Speed; Stress; Syndrome; Testing; Variant; cardiovascular disorder risk; congenic; density; diabetic; diabetic patient; genome-wide; mortality; programs; public health relevance

DESCRIPTION (provided by applicant): Over 400,000 Americans have end-stage renal disease (ESRD) requiring dialysis or kidney transplant for survival. ESRD in the US population doubled in the last decade and this increase is driven by diabetes and hypertension. ESRD is associated with very high rates of mortality, most frequently from cardiovascular disease (CVD), and the heightened risk of CVD in individuals with chronic renal injury means that they are much more likely to die of CVD than to progress to ESRD. There is great variation in risk for ESRD among individuals who have hypertension and/or diabetes. The major determinant of this variation in risk is genetic susceptibility that serves to enhance the capacity of hypertension and diabetes to generate renal injury. The proposed studies focus on an animal model of renal injury with concurrent hypertension, insulin resistance and dyslipidemia, the spontaneously hypertensive rat (SHR). This model recapitulates the role of genetic susceptibility to renal injury in hypertensive and diabetic patients: the SHR-A3 line acquires hypertensive renal injury, while other hypertensive SHR lines resist it. These contrasting SHR lines offer a valuable means to identify the mechanism of and the genes contributing to susceptibility to renal injury. The proposed studies are made possible by our recent progress in defining a set of high density, single nucleotide polymorphism (SNP) markers in our injury-prone (SHR-A3) and resistant (SHRB2) lines that allow high resolution genetic mapping of loci controlling susceptibility to renal injury. We propose here to use these markers to map an intercross of these parental lines that will identify injury susceptibility loci. The conclusions of our mapping study will be tested and verified by breeding reciprocal congenic strains that fix injury resistance and susceptibility alleles in the injury-prone SHR-A3 and the injury-resistant SHR-B2 lines. Finally, we have uncovered the role of renal redox stress in the generation of renal injury in SHR-A3 and identified a transcriptional program that leads to this redox stress. This provides an opportunity to refine our genetic mapping studies down to the level of specific genes within the mapped loci. Genes that are functionally correlated to the transcriptional pathway of renal redox stress that we have elucidated in SHR-A3 will be targeted for selective resequencing to identify specific gene variants that drive the renal injury pathway. PUBLIC HEALTH RELEVANCE Kidney injury caused by diabetes and high blood pressure requires that more than 400,000 Americans be treated by kidney dialysis in order to survive. Heredity plays a major role in risk of kidney injury. Among diabetic and high blood pressure patients, the largest risk of progressive kidney disease is the occurrence of this disease in a relative. In the proposed studies we will use a rat model of this syndrome to genetically map chromosomal regions harboring genes that create risk of kidney injury. By uncovering the genes that cause this injury in rats and how this injury is created by these genes we will open up valuable new opportunities to understand the disease in people and to envision and test new treatments.

描述（由申请人提供）：超过40万名美国人患有终末期肾脏疾病（ESRD），需要透析或肾脏移植才能生存。在过去的十年中，美国人口的ESRD翻了一番，这一增加是由糖尿病和高血压驱动的。 ESRD与非常高的死亡率有关，最常见于心血管疾病（CVD），并且患有慢性肾脏损伤患者CVD的风险增加意味着他们死于CVD比ESRD更可能死于CVD。患有高血压和/或糖尿病的个体的ESRD风险有很大差异。这种风险差异的主要决定因素是遗传敏感性，可提高高血压和糖尿病的能力产生肾脏损伤。拟议的研究集中于同时发生高血压，胰岛素抵抗和血脂异常，自发性高血压大鼠（SHR）的肾脏损伤模型。该模型概括了遗传对肾脏损伤在高血压和糖尿病患者中的作用：SHR-A3系列可获得高血压的肾脏损伤，而其他高血压SHR线则抵抗了肾脏损伤。这些对比的SHR线提供了一种有价值的手段，可以识别导致肾脏损伤易感性的基因和基因。我们最近在定义一组高密度，单核苷酸多态性（SNP）标志物（SHR-A3）和抗性（SHRB2）线（SHRB2）线方面的进展，使提出的研究成为可能。我们在这里建议使用这些标记来绘制这些父母线的间折叠，以识别损伤易感性位点。我们的映射研究的结论将通过繁殖相互抗性的菌株来测试和验证，这些菌株固定耐损伤和容易受伤的SHR-A3和耐损伤的SHR-B2线。最后，我们发现了肾脏氧化还原应激在SHR-A3中肾脏损伤产生中的作用，并确定了导致这种氧化还原应激的转录程序。这提供了将我们的基因映射研究改进到映射基因座内特定基因水平的机会。与我们在SHR-A3中阐明的肾脏氧化还原应力的转录途径在功能上相关的基因将被靶向选择性重新方程，以识别驱动肾脏损伤途径的特定基因变体。糖尿病和高血压引起的公共卫生相关性肾脏损伤要求肾脏透析治疗超过40万名美国人以生存。遗传在肾脏受伤的风险中起着重要作用。在糖尿病患者和高血压患者中，进行性肾脏疾病的最大风险是亲戚中发生这种疾病。在拟议的研究中，我们将使用该综合征的大鼠模型来遗传构图具有产生肾脏损伤风险的基因的染色体区域。通过发现造成大鼠损伤的基因以及这些基因如何造成这种伤害，我们将为了解人们的疾病并设想和测试新疗法的宝贵新机会。