Development of novel strategies for the treatment of neurogenic cardiovascular disease (CVD) requires a detailed understanding of the long-term controllers of sympathetic nerve activity (SNA). Advances in this field require research at the genomic, cellular, neural network and whole animal levels. The ability of a single laboratory, or institution, to carry out this task is difficult if not impossible. We propose the formation of an inter-institutional Consortium to advance our understanding of the neurogenic basis of CVD with the initial focus on the angiotensin II (Angll)-salt model of hypertension (HTN). There are 3 Specific Aims.
In Aim 1 we will identify brain site(s) that mediate changes in SNA in the Angll-salt model, establish genes in those sites whose expressions change in concert with the HTN, and discern how alterations in excitatory and inhibitory inputs to these sites alter the gene expression profile, SNA, and mean arterial pressure (MAP). We will use viral gene transfer to normalize the gene expression profile, SNA, and MAP in Ang-salt HTN.
In Aim 2 we will establish how Angll and dietary salt cause time-dependent, differential regional SNA and blood flow changes in conscious rats. These studies will establish the importance of capacitance and resistance changes, as well as specific contributions of the renal, splanchnic and hindlimb vascular beds in mediating Angll-salt HTN.
In Aim 3 we will determine how disruption of sensory inputs linked to dietary salt and Angll affect the pathways characterized in Aim 1, and the SNA and cardiovascular response patterns characterized in Aim 2. We feel this integrative approach will provide fertile ground for the development of a greater understanding of the mechanisms that link the nervous system and CVD. We are confident that the inter-institutional collaboration of the Consortium will lead to new perspectives and answers that will ultimately lead to the development of novel genetic-based therapies for neurogenic HTN not achievable using more conventional insular approaches.
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