Autoregulation of Cerebral Blood Flow

描述（由申请人提供）：存在大量关于负责脑血流量（CBF）自动调节的压力诱导肌源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肌源性张力的机制的理解却知之甚少。在本申请中，我们描述了一种动物模型，其中一种大鼠品系，Fawn Hooded大鼠（FHH）在面对动脉压增加时不会自动调节CBF，然而，经过9代繁殖的多年同源体杂交，我们发现转移Brown Norway（BN）大鼠1号染色体上的区域恢复了FHH. 1BN同源体大鼠中的肌原性表型。很明显，1号染色体上的一个位点含有一个基因，该基因编码触发肌源性张力，以响应动脉压的变化。3-5多年来对1号染色体的选择性操作和杂交后代的F1代的表型分析已经将该染色体的区域缩小到1.2M碱基对的数量性状基因座（QTL），其含有内收蛋白3（Add 3）和DUSP-5的基因沿着其它不完整的基因。这个1.2 M碱基QTL的转移赋予FHH大鼠正常的自动调节表型。使用siRNA方法敲低Add 3和DUSP-5，在初步实验中，我们通过敲低Add 3和DUSP-5蛋白水平显著降低了自动调节能力。本申请中描述的方案被设计用于定义负责该1.2M碱基QTL中Add 3、DUSP-5或其他尚未鉴定的基因的作用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，这是必要的启动和维持压力诱导的肌张力的离子种类。这些大鼠品系是同类动物模型，允许鉴定负责压力诱导的自身调节的机制，其中不可能发生背景基因型的代偿性变化，这与敲除小鼠中可能发生的情况不同。 公共卫生相关性：使用拨款申请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脑血流量自动调节的信号事件和离子机制。这些信息将有助于开发更好的未来治疗方案，用于神经血管相关疾病，如中风，创伤性脑损伤，老年痴呆症和老年痴呆症。

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.