Impaired Myogenic Response and Risk of Renal and Vascular Disease with Aging

随着年龄的增长，肌源性反应受损以及肾脏和血管疾病的风险

• 批准号: 8127475
• 负责人: Marilyn Burke
• 金额: $ 2.58万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127475
• 关键词: Accounting; Acute; Age; Aging; Alzheimer' s Disease; Animal Model; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain hemorrhage; Candidate Disease Gene; Caring; Cerebral Edema; Cerebrovascular Circulation; Cerebrum; Chromosomes, Human, Pair 1; Chronic Disease; Comorbidity; Congenic Strain; Cytoskeleton; DNA Sequence; Data; Development; Diabetes Mellitus; Dialysis procedure; Disease; Elderly; End stage renal failure; Exhibits; Fingers; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Models; Glomerular Capillary; Goals; Government; Homeostasis; Hydrostatic Pressure; Hypertension; Impaired cognition; Impairment; In Vitro; Inbred BN Rats; Incidence; Individual; Injury; Institution; Ion Channel; Ischemic Stroke; Kidney; Kidney Diseases; Knock-out; Lead; MAP Kinase Gene; Membrane Protein Traffic; Molecular; Molecular Biology; Molecular Genetics; Mutation; Nervous System Trauma; Pathway interactions; Patients; Perfusion; Phenotype; Play; Population; Positioning Attribute; Postdoctoral Fellow; Prevention; Progressive Disease; Protein Serine/Threonine Phosphatase; Proteinuria; Rattus; Regulation; Renal Blood Flow; Renal Circulation; Research; Research Methodology; Research Training; Risk; Role; Small Interfering RNA; Smooth Muscle; Stroke; Survivors; Techniques; Transgenic Organisms; Traumatic Brain Injury; Variant; Vascular Dementia; Vascular Diseases; Work; artery occlusion; base; capillary; congenic; cost; diabetic; diabetic patient; experience; in vivo; inhibitor/antagonist; insight; interest; knockout gene; novel; nuclease; pressure; response

DESCRIPTION (provided by applicant): The myogenic response is a critical homeostatic mechanism of vasculature smooth muscle that maintains constant blood flow and capillary pressure to the brain and kidney despite fluctuations in perfusion pressure. There is evidence that the myogenic response is impaired in aging populations, especially in the presence of comorbidities of hypertension and diabetes. Hypertension and diabetes are leading causes of end stage renal disease (ESRD) and stroke; however, not all hypertensive or diabetic patients develop ESRD or stroke and very little is known about the genetic factors that determine an individual's risk. The Fawn Hooded Hypertensive (FHH) rat is a genetic model of hypertension and ESRD. We have shown that they exhibit an impaired myogenic response in both renal and cerebral circulation with aging. However, the genes and pathways involved are unknown. The goals of this project are to use molecular, genetic and transgenic approaches to identify the gene and associated pathways responsible for impaired myogenic response in FHH rats. The 1st aim of this project is to characterize a congenic FHH.1BN strain with a narrowed region of interest for myogenic response in renal and cerebral vessels. The 2nd aim is to perform DNA sequencing and PCR expression studies of all the genes in the region to obtain the molecular evidence needed to prioritize which of the positional candidate genes to investigate further. The 3rd aim is to evaluate the ability of sequence variants in Add3 and Dusp5 and any other positional candidate genes to alter myogenic tone in the renal and cerebral vasculature of FHH rats using a transposon-based transgenic rescue, targeted Zn-finger nuclease gene knockout strategies and siRNA knockdown techniques in the FHH genetic background. The research training and methods related to these aims will provide me with experience using techniques ranging from in vivo and vitro studies of vascular function to cutting edge molecular biology and transgenic manipulation. Completion of these studies will put me in a very competitive position to obtain a post-doc position at a well respected research institution to continue work on the genetic basis of vascular disease. PUBLIC HEALTH RELEVANCE: With an increasing elderly population in the U.S., there is increasing incidence and cost of treating chronic and progressive diseases such as hypertension and diabetes which are predictors of other serious and costly conditions; notably stroke and end stage renal disease (ESRD). There are around 750,000 strokes annually in the US with an estimated cost of caring for survivors at $51 billion annually. Hypertension and diabetic induced ESRD disease, traditionally considered a disease of old age, now accounts for over 67% of US cases with a cost to the US government of over $20 billion a year for dialysis alone.

描述（由申请人提供）：肌源性反应是血管平滑肌的关键稳态机制，尽管灌注压波动，但其仍维持恒定的脑和肾血流和毛细血管压。有证据表明，在老年人群中，特别是在存在高血压和糖尿病合并症的情况下，肌源性反应受损。高血压和糖尿病是终末期肾病（ESRD）和中风的主要原因;然而，并非所有高血压或糖尿病患者都会发展为ESRD或中风，并且对决定个体风险的遗传因素知之甚少。Fawn Hooded Hypertensive（FHH）大鼠是高血压和ESRD的遗传模型。我们已经表明，他们表现出受损的肌源性反应，在肾脏和脑循环随着年龄的增长。然而，涉及的基因和途径是未知的。本项目的目标是利用分子、遗传和转基因的方法来鉴定FHH大鼠肌源性反应受损的基因和相关通路。本项目的第一个目的是表征在肾血管和脑血管中肌源性反应的感兴趣区域变窄的同类FHH. 1BN菌株。第二个目标是对该区域的所有基因进行DNA测序和PCR表达研究，以获得所需的分子证据，从而优先考虑进一步研究的位置候选基因。第三个目的是在FHH遗传背景下，使用基于转座子的转基因拯救、靶向锌指核酸酶基因敲除策略和siRNA敲除技术，评价Add 3和Dusp 5中的序列变体以及任何其他位置候选基因改变FHH大鼠肾和脑血管系统中肌原性张力的能力。与这些目标相关的研究培训和方法将为我提供使用从血管功能的体内和体外研究到尖端分子生物学和转基因操作的技术的经验。完成这些研究将使我处于一个非常有竞争力的位置，在一个备受尊敬的研究机构获得博士后职位，继续研究血管疾病的遗传基础。 公共卫生相关性：随着美国老年人口的增加，治疗慢性和进行性疾病（例如高血压和糖尿病）的发病率和费用不断增加，高血压和糖尿病是其它严重和昂贵疾病的预测因子;特别是中风和终末期肾病（ESRD）。美国每年约有75万人中风，估计每年照顾幸存者的费用为510亿美元。高血压和糖尿病引起的ESRD疾病，传统上被认为是老年疾病，现在占美国病例的67%以上，美国政府每年仅透析费用就超过200亿美元。