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.
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.
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