Recent studies by others and pilot experiments presented here raise the hypothesis that adipocyte production of angiotensinogen could be causally related to obesity-associated hypertension. This hypothesis will be tested by: 1) screening animal models of obesity and hypertension to identity those where adipose tissue elevation of angiotensinogen production/secretion correlate with hypertension, 2) testing the fidelity of this correlation in the temporal development of obesity and under various dietary regimens, 3) evaluating hormonal regulation of adipose tissue angiotensinogen in vivo and in vitro, and 4) identifying the molecular mechanisms controlling the expression of angiotensinogen mRNA. If data from these investigations. support the hypothesis, humans studies will be initiated to establish the clinical significance of adipocyte angiotensinogen. The research environment is strongly positioned to train Robert to become a productive independent investigator, and uniquely suited to pursue this project. Dr. Flier's laboratory is well equipped, and the group he heads has a strong commitment to understanding and treating obesity, and its related morbidity. Dr. Flier's work in adipsin, the fat-specific differentiation-dependent serine protease which is regulated by diet, and abnormal in genetic and hypothalamic rodent models of obesity exemplifies his commitment to creative approaches to this problem. The Beth Israel Endocrinology division has a strong emphasis on the study of obesity, notably containing Drs. Landsberg and Young, who have themselves made contributions to understanding hypertension of the obese. The collaborators, Dr. Spiegelman, and Dr. Habener are outstanding investigators who have arguably made the greatest contributions to understanding adipocyte differentiation, and, angiotensinogen expression, respectively at the molecular level.
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