Autoregulation of Cerebral Blood Flow

脑血流的自动调节

• 批准号: 8584314
• 负责人: David Rae Harder
• 金额: $ 59.7万
• 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/8584314
• 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.

描述(由申请人提供)：关于压力诱导的脑血流(CBF)自动调节的肌源性调节的细胞和离子机制，有大量的文献。然而，我们对压力激活动脉壁肌源性张力的机制还知之甚少。在这个应用中，我们描述了一个动物模型，在这个动物模型中，面对不断增加的动脉压，一只大鼠品系Fawn Hooded rat(FHH)不能自动调节CBF，然而，经过9代的家系杂交，我们发现转移一只棕色挪威(BN)大鼠1号染色体上的一个区域，恢复了FHH.1BN家系大鼠的肌源性表型。很明显，1号染色体上的一个基因包含一个基因，该基因编码了触发肌张力以响应动脉压变化的基因。经过3-5年对1号染色体的选择性操作和F1代杂交后代的表型鉴定，已将该染色体的范围缩小到一个1.2M碱基对的数量性状基因座(QTL)，该QTL包含内收蛋白3(Add3)和DUSP-5基因以及其他不完全基因。转移这个1.2M碱基的QTL赋予FHH大鼠正常的自我调节表型。使用siRNA方法敲除Add3和DUSP-5，我们在初步实验中，通过击倒Add3和DUSP-5蛋白水平，显著降低了自动调节能力。本申请中描述的协议旨在定义负责ADD3、DUSP-5或其他尚未识别的基因在这个1.2M碱基QTL中的作用的细胞信号级联。同样，我们将确定负责压力诱导的膜去极化的离子物种，这是启动和维持压力诱导的肌源性张力所必需的。这些大鼠品系是同源动物模型，可以识别压力诱导自动调节的机制，在这种模型中，背景基因不会发生补偿性变化，不像基因敲除小鼠那样。