Autoregulation of Cerebral Blood Flow

脑血流的自动调节

• 批准号: 8236714
• 负责人: David Rae Harder
• 金额: $ 63.57万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-05 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236714
• 关键词: Alzheimer' s Disease; Animal Model; Applications Grants; Backcrossings; Base Pairing; Biological Models; Blood Vessels; Blood flow; Breeding; Candidate Disease Gene; Cerebrovascular Circulation; Cerebrum; Chromosomes; Chromosomes, Human, Pair 1; Code; Congenic Animals; Congenic Strain; Data; Disease; Event; Exhibits; Figs - dietary; Future; Generations; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genotype; Grant; Homeostasis; Human; Hydroxyeicosatetraenoic Acids; Knockout Mice; Knowledge; Left; Link; Literature; MAP Kinase Gene; Maintenance; Mediating; Membrane; Methodology; Modeling; Muscle; Mutate; Nature; Phenotype; Play; Property; Protein Tyrosine Kinase; Protein phosphatase; Proteins; Protocols documentation; Quantitative Trait Loci; Rat Strains; Rattus; Rattus norvegicus; Recovery; Regulation; Reporting; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Specificity; Stretching; Stroke; TRP channel; Techniques; Traumatic Brain Injury; Work; adducin; aging population; base; comparative; congenic; consomic; constriction; design; genetic linkage; interest; knock-down; large-conductance calcium-activated potassium channels; offspring; pressure; research study; response; restoration; tool

DESCRIPTION (provided by applicant): There exists a substantial amount of literature regarding the cellular and ionic mechanisms responsible for pressure-induced myogenic regulation of cerebral blood flow (CBF) autoregulation. However, our understanding of the mechanisms by which pressure activates myogenic tone in the arterial wall is only poorly understood. We describe in this application an animal model in which one rat strain, the Fawn Hooded rat (FHH) does not auto regulate CBF in the face of an increasing arterial pressure, whereas, years of consomic interbreeding of 9 generation breeding we found that transfer of a region on chromosome 1 of a Brown Norway (BN) rat recovered the myogenic phenotype in the FHH.1BN consomic rat. It became clear that a locus on chromosome 1 contained a gene coding for the trigger of myogenic tone in response to changes in arterial pressure. 3-5 years of selective manipulation of chromosome 1 and phenotyping F1 generations of interbred offspring have narrowed the region of this chromosome to a 1.2 M base pair quantitative trait loci (QTL) containing the gene for adducin3 (Add3) and DUSP-5 along with other incomplete genes. Transfer of this 1.2 M base QTL confers a normal auto regulatory phenotype in the FHH rat. Using siRNA methodology to knockdown Add3 and DUSP-5 we have, in preliminary experiments, significantly reduced auto regulatory capacity by knocking down Add3 and DUSP-5 protein levels. Protocols described in this application are designed to define the cellular signaling cascades responsible for the actions of Add3, DUSP-5 or other yet unidentified genes in this 1.2 M base QTL. Similarly, we will identify the ionic species responsible for pressure-induced membrane depolarization which is necessary for initiation and maintenance of pressure-induced myogenic tone. These rat strains are the congenic animal model allowing identification of the mechanisms responsible for pressure-induced autoregulation in which no compensatory changes in the background genotype can occur, unlike that which can occur in a knockout mouse. PUBLIC HEALTH RELEVANCE: The proposed work using the genetic model of rat described in the grant application will aid us in identifying signaling events and ionic mechanisms that controls the myogenic tone and the autoregulation of cerebral blood flow. This information will help in developing better future treatment options for neurovascular related diseases such as stroke, traumatic brain injury, dementia and Alzheimers in aging population of humans.

描述（由申请人提供）：关于负责压力诱导的脑血流（CBF）自动调节的细胞和离子机制，存在大量文献。但是，我们对压力在动脉壁中激活肌吻合的机制的理解仅了解。我们在此应用中描述了一种动物模型，其中一种大鼠菌株，小鹿帽鼠（FHH）不会在动脉​​压的增加时自动调节CBF，而多年来，我们发现9代繁殖的多年杂质杂交繁殖的多年。棕色挪威（BN）大鼠染色体1上的一个区域在FHH中恢复了肌源性表型。很明显，染色体上的一个基因座包含一个基因编码，以响应动脉压的变化而造成肌吻合的触发器。 3 - 5年的选择性操纵1染色体1和表型F1世代间的杂种后代将该染色体的区域范围缩小到1.2 m的碱基对定量性状基因座（QTL），其中含有Adducin3（Add3）和Dusp-5的基因，以及DUSP-5的基因其他不完整的基因。该1.2 m基QTL的转移赋予FHH大鼠中正常的自动调节表型。在初步实验中，使用siRNA方法敲除ADD3和DUSP-5，通过击倒ADD3和DUSP-5蛋白水平，我们具有显着降低自动调节能力。本应用程序中描述的协议旨在定义负责ADD3，DUSP-5或其他未知基因的细胞信号传导级联。同样，我们将确定负责压力诱导的膜去极化的离子物种，这对于启动和维持压力诱导的肌源性张力是必需的。这些大鼠菌株是允许识别负压引起的自动调节的机制的先天动物模型，在这种机制中，背景基因型中没有代偿性变化，这与敲除小鼠中可能发生的机制可能发生。 公共卫生相关性：使用赠款应用中描述的大鼠遗传模型的拟议工作将有助于我们识别控制肌源性张力和自动调节大脑血流的信号事件和离子机制。这些信息将有助于为神经血管相关疾病（例如中风，脑损伤，痴呆症和阿尔茨海默氏症）的神经血管相关疾病提供更好的治疗选择。