Hypertensive Renal Injury
高血压肾损伤
基本信息
- 批准号:7938592
- 负责人:
- 金额:$ 35万
- 依托单位:
- 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:2009-09-25 至 2012-07-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesAmericanAnimal ModelBreedingCardiovascular DiseasesChromosome MappingChronicCongenic StrainControl LocusDNA ResequencingDiabetes MellitusDialysis procedureDiseaseDyslipidemiasEnd stage renal failureGenerationsGenesGenetic Predisposition to DiseaseGenetic VariationHeredityHypertensionInbred SHR RatsIndividualInjuryInsulin ResistanceKidneyKidney DiseasesKidney TransplantationMapsModelingOxidation-ReductionPathway interactionsPatientsPlayPopulationPredispositionRattusRelative (related person)Renal dialysisResistanceResolutionRiskRoleSingle Nucleotide PolymorphismSpeedStressSyndromeTestingVariantcardiovascular disorder riskcongenicdensitydiabeticdiabetic patientgenome-widemortalityprogramspublic health relevance
项目摘要
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 400,000 名美国人患有终末期肾病 (ESRD),需要透析或肾移植才能生存。过去十年,美国人口的终末期肾病 (ESRD) 翻了一番,这种增长是由糖尿病和高血压推动的。 ESRD 与非常高的死亡率相关,最常见的是心血管疾病 (CVD),而患有慢性肾损伤的个体 CVD 风险较高,这意味着他们死于 CVD 的可能性比进展为 ESRD 的可能性要高得多。高血压和/或糖尿病患者的终末期肾病 (ESRD) 风险存在很大差异。这种风险差异的主要决定因素是遗传易感性,遗传易感性会增强高血压和糖尿病造成肾损伤的能力。拟议的研究重点是并发高血压、胰岛素抵抗和血脂异常的肾损伤动物模型,即自发性高血压大鼠(SHR)。该模型概括了遗传易感性对高血压和糖尿病患者肾损伤的作用:SHR-A3 系获得高血压肾损伤,而其他高血压 SHR 系则抵抗它。这些对比 SHR 系提供了一种有价值的方法来识别肾损伤的机制和导致肾损伤易感性的基因。我们最近在易损伤 (SHR-A3) 和抗性 (SHRB2) 品系中定义了一组高密度单核苷酸多态性 (SNP) 标记,这些标记允许对位点控制进行高分辨率遗传图谱,从而使拟议的研究成为可能易受肾损伤。我们在这里建议使用这些标记来绘制这些亲本系的杂交图,从而识别损伤易感性位点。我们的图谱研究的结论将通过培育互惠同源菌株来测试和验证,这些菌株修复易受损伤的 SHR-A3 和抗损伤 SHR-B2 系中的损伤抗性和易感性等位基因。最后,我们发现了肾氧化还原应激在 SHR-A3 肾损伤产生中的作用,并确定了导致这种氧化还原应激的转录程序。这提供了将我们的遗传图谱研究细化到所绘制基因座内的特定基因水平的机会。我们在 SHR-A3 中阐明的与肾氧化还原应激转录途径功能相关的基因将被选择性重测序,以鉴定驱动肾损伤途径的特定基因变异。公共卫生相关性 糖尿病和高血压引起的肾损伤需要超过 400,000 名美国人接受肾透析治疗才能生存。遗传在肾损伤风险中起着重要作用。在糖尿病和高血压患者中,进展性肾病的最大风险是亲属中发生这种疾病。在拟议的研究中,我们将使用这种综合征的大鼠模型来对含有产生肾损伤风险的基因的染色体区域进行基因定位。通过揭示导致大鼠这种损伤的基因以及这些基因如何造成这种损伤,我们将为了解人类疾病并设想和测试新的治疗方法开辟宝贵的新机会。
项目成果
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PETER A DORIS其他文献
PETER A DORIS的其他文献
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{{ truncateString('PETER A DORIS', 18)}}的其他基金
Long-read assembly and annotation of rat genomes that are important models of complex genetic disease
大鼠基因组的长读组装和注释是复杂遗传疾病的重要模型
- 批准号:
10211748 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Long-read assembly and annotation of rat genomes that are important models of complex genetic disease
大鼠基因组的长读组装和注释是复杂遗传疾病的重要模型
- 批准号:
10615135 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Long-read assembly and annotation of rat genomes that are important models of complex genetic disease
大鼠基因组的长读组装和注释是复杂遗传疾病的重要模型
- 批准号:
10211748 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Long-read assembly and annotation of rat genomes that are important models of complex genetic disease
大鼠基因组的长读组装和注释是复杂遗传疾病的重要模型
- 批准号:
10449388 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
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