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）：存在大量关于负责脑血流（CBF）自动调节的压力诱导的肌原性调节的细胞和离子机制的文献。然而，我们对压力激活动脉壁生肌张力的机制了解甚少。我们在本申请中描述了一种动物模型，其中一种大鼠品系，小鹿连帽大鼠（FHH）在面临动脉压增加时不会自动调节CBF，而经过多年的9代同体杂交，我们发现棕色挪威（BN）大鼠1号染色体上的一个区域的转移恢复了FHH.1BN同体大鼠的肌源表型。很明显，1 号染色体上的一个基因座含有一个基因，该基因编码可触发肌源性张力，以响应动脉压的变化。对 1 号染色体进行 3-5 年的选择性操作并对杂交后代的 F1 代进行表型分析，已将该染色体的区域缩小到 1.2 M 碱基对数量性状位点 (QTL)，其中包含内收蛋白 3 (Add3) 和 DUSP-5 基因以及其他不完整基因。该 1.2 M 碱基 QTL 的转移赋予 FHH 大鼠正常的自动调节表型。在初步实验中，我们使用 siRNA 方法敲低 Add3 和 DUSP-5，通过敲低 Add3 和 DUSP-5 蛋白水平，显着降低了自动调节能力。本申请中描述的方案旨在定义负责此 1.2 M 碱基 QTL 中 Add3、DUSP-5 或其他尚未鉴定的基因的作用的细胞信号级联。同样，我们将确定负责压力诱导膜去极化的离子种类，这对于压力诱导肌原性张力的启动和维持是必要的。这些大鼠品系是同类动物模型，可以鉴定负责压力诱导的自动调节的机制，其中背景基因型不会发生补偿性变化，这与基因敲除小鼠中可能发生的情况不同。 公共健康相关性：拟议的使用拨款申请中描述的大鼠遗传模型的工作将帮助我们识别控制肌源张力和脑血流自动调节的信号事件和离子机制。这些信息将有助于为老年人口中的神经血管相关疾病（如中风、创伤性脑损伤、痴呆和阿尔茨海默病）开发更好的未来治疗方案。