The long term objective of the research proposed in this continuation remains to help unravel the genetic complexities of essential hypertension. For the coming grant period, we have chosen three aims:
Specific aim (i) will complete or extend our quantitative analyses to include titrations of the genes coding for: renin (Ren-1), aldosterone synthase (Cyp11b2), adrenomedullin (Adm) and its receptor (Ca/cr1). the calcitonin receptor like receptor. Blood pressures will be determined and quantitative RT-PCR will be used to assess the degree to which homeostatic compensations have been induced. The effects of environmental changes, such as dietary salt and pregnancy, will be investigated. Our expectation is that these analyses will identify additional genes predicted to cause changes in blood pressure or its homeostasis if their expression varies as a result of genetic polymorphisms in humans.
Specific aim (ii) will explore a new problem--how blood pressure and its homeostasis are affected by combining high expressing and low expressing genetic variants within the same physiologic system (for example Agt & Agtr1a) and in different systems (for example Agt & Npr1). We will breed currently available animals to give four combinations (high & high, high & low, low & high and low & low) for each pair of genes. We will develop computer simulations that include interactions between different systems, and will compare them with experimental data. Any inadequacies revealed will facilitate improvement of the models. This to-and-fro process is expected to greatly increase current understanding of why some combinations of genetic variations are detrimental and others beneficial.
Specific aim (iii) will investigate the mechanisms underlying highly significant gender-related differences that we have found occur (a) in the expression and responses of more than 10 genes related to the control of blood pressure; (b) in the relationship between blood pressure and variations in the liver expression of Agt that are unrelated to gene copy number, and (c) between kidney expression of Agtr1a and Kiki, the gene coding for kallikrein. All three of these gender effects have direct relevance to humans, and we expect that their analysis will reveal some previously unknown causes underlying the differences in cardiovascular risk factors in males and pre-menopausal females.
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