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Genetics of Renal End Organ Damage in Hypertension

高血压肾终末器官损伤的遗传学

基本信息

批准号：
8477235
负责人：
MICHAEL R GARRETT
金额：
$ 35.23万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
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：
2009-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477235
关键词：
1q21 Accounting Albumins Alleles Animals Biological Assay Blood Glucose Blood Pressure Breeding Candidate Disease Gene Cardiovascular system Cell Line Cells Chromosomes, Human, Pair 2 Code Complex Complex Genetic Trait Congenic Strain Development Diabetes Mellitus Dialysis procedure Diploidy Disease Disease Progression Disease model End stage renal failure Epithelial Evaluation Event Exhibits Expenditure Fibrosis Filtration Focal Segmental Glomerulosclerosis Functional disorder Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Techniques Genetic Variation Genome Genome Scan Genomics Glomerular Capillary Goals Haplotypes Health Human Human Chromosomes Human Genetics Human Genome Hypertension In Vitro Inbred SHR Rats Inbred Strains Rats Inbreeding Incidence Inflammation Injury Insurance Kidney Kidney Diseases Kidney Failure Knowledge Link Measurement Measures Mediating Medicare Mesenchymal Modeling Mutation Nephrotic Syndrome Organ Pathway interactions Patients Permeability Phase Physiological Play Population Preparation Primary Cell Cultures Production Proteins Proteinuria Quantitative Trait Loci Rattus Recombinants Renal Blood Flow Renal function Research Resistance Rodent Model Role Sequence Analysis Signal Transduction Staging Structure Subfamily lentivirinae Susceptibility Gene System Testing Time Transcript Transplantation Tubular formation United States Validation Variant Western Blotting Work abstracting arteriole base blood pressure regulation comparative congenic cost design economic impact effective therapy genetic analysis genetic linkage analysis genetic variant glomerular filtration glomerular function hemodynamics human disease in vitro testing in vivo interest interstitial kidney cell lentiviral-mediated overexpression podocyte population based pressure prevent protein expression research study response salt sensitive success trait transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Abstract There is an alarming increase in the incidence of end-stage renal disease in the Unites States, with hypertension and diabetes being the major cause. Currently, 25.6 million people are in the early phase of kidney disease (stage 1 to 3) and while strict control of blood pressure and glucose levels may slow, it will not prevent the progressive decline of renal function in these patients. Therefore, understanding the genetic basis of hypertension-induced renal disease is of considerable interest. Significant progress has been made to identify the genetic causes of familial forms of renal disease (nephrotic syndrome). However, no genetic variants have been found to be causally linked to common forms of renal disease. It is our goal to develop a better understanding of the genetic basis of hypertension-induced renal disease observed in the Dahl salt- sensitive (S) rat, which exhibits significant proteinuria and focal segmental glomerulosclerosis (FSGS). An initial genetic analysis for proteinuria and renal injury was performed using a population derived from the S. The study identified ten genomic regions linked to renal damage (measured by proteinuria) and/or function. A congenic strain developed on chromosome 2 exhibited significantly less proteinuria and FSGS. This proposal will evaluate the hypothesis that genetic variant(s) located to a small region on rat chromosome 2 play a significant role in the progressive FSGS and proteinuria observed in the S rat. Based on congenic strain analysis, the causative locus has been narrowed to <1.2 Mbs containing 27 genes. However, cross-species comparative, inbred-based SNP analysis, comprehensive coding sequence and gene expression analysis has convincingly identified 4 genes for further study. The aims of the proposed study are: (1) to perform temporal studies of blood pressure and renal hemodynamics, including renal blood flow, glomerular capillary pressure, and glomerular permeability in the S and small congenic strain; (2) to perform comprehensive gene expression, western blot analysis, sequencing, and haplotype analysis for genes narrowed to the small region on rat chromosome 2; and (3) to evaluate the functional significance of identified allelic variants using cell- based and whole-animal approaches. In summary, this proposal will identify and prioritize gene(s) linked to proteinuria and FSGS in the Dahl S model of hypertension-induced renal disease and provide a basis for functional studies, gene validation, and eventually study in human-based populations.

描述（由申请人提供）：摘要在美国，终末期肾病的发病率正在惊人地增加，其中高血压和糖尿病是主要原因。目前，有2560万人处于肾脏疾病的早期阶段（1至3期），虽然严格控制血压和血糖水平可能会减缓这些患者的肾功能逐渐下降的速度，但并不能阻止这些患者的肾功能逐渐下降。因此，了解高血压引起的肾脏疾病的遗传基础具有相当大的意义。在确定家族性肾病（肾病综合征）的遗传原因方面已取得重大进展。然而，尚未发现遗传变异与常见形式的肾脏疾病存在因果关系。我们的目标是更好地了解在 Dahl 盐敏感 (S) 大鼠中观察到的高血压诱发的肾病的遗传基础，该大鼠表现出显着的蛋白尿和局灶节段性肾小球硬化 (FSGS)。使用来自 S 的群体进行了蛋白尿和肾损伤的初步遗传分析。该研究确定了与肾损伤（通过蛋白尿测量）和/或功能相关的 10 个基因组区域。在 2 号染色体上发育的同源菌株表现出明显较少的蛋白尿和 FSGS。该提案将评估以下假设：位于大鼠 2 号染色体小区域的遗传变异在 S 大鼠中观察到的进行性 FSGS 和蛋白尿中发挥重要作用。根据同源菌株分析，致病位点已缩小至包含 27 个基因的 <1.2 Mbs。然而，跨物种比较、基于近交的 SNP 分析、综合编码序列和基因表达分析已令人信服地鉴定出 4 个基因可供进一步研究。本研究的目的是：(1) 对 S 型和小同源型菌株的血压和肾血流动力学进行时间研究，包括肾血流量、肾小球毛细血管压力和肾小球通透性； (2)对大鼠2号染色体上的小区域基因进行全面的基因表达、蛋白质印迹分析、测序和单倍型分析； (3) 使用基于细胞和整体动物的方法评估已识别等位基因变异的功能意义。总之，该提案将在高血压诱发的肾病 Dahl S 模型中识别并优先考虑与蛋白尿和 FSGS 相关的基因，并为功能研究、基因验证和最终在人类人群中的研究提供基础。