The Mentored Clinical Scientist Developmental Award described in this application is designed to provide the applicant broad experience in the application of modern technology to understanding the role of guanylyl cyclases in cell signaling and how these receptors participate in the regulation of salt homeostasis and blood pressure. This experience will permit him to establish a career as an independent investigator. The candidate obtained his subspecialty clinical and research training in the Division of Pediatric Gastroenterology and Nutrition at the Floating Hospital for Infants and Children, at Tufts University School of Medicine, Boston. In order to study the role the receptor guanylyl cyclases in cell signaling and how they participate in renal and vascular smooth muscle function in disease and health, the candidate chose to develop skills in molecular biology and physiology. Support of his research in the Department of Pediatrics provides an ideal arrangement for continued growth toward an independent career in basic research sponsored by David L. Garbers, Ph.D., Professor of Pharmacology, Patrick E. Haggerty Distinguished Chair in Basic Biomedical Science, Howard Hughes Medical Institute Investigator, a highly regarded investigator in the field of cGMP and guanylyl cyclases. Atrial natriuretic peptide (ANP) infusions in animals or humans result in natriuresis/diuresis and vasodilatation. Circumstantial evidence suggests that guanylyl cyclase-A (GC-A) is the receptor for ANP. However, physiological studies and gene disruption of the ligand ANP suggest a central role for ANP in salt excretion, but mice lacking GC-A develop salt-resistant hypertension and excrete salt normally. Preliminary data suggest that ANP no longer causes natriuresis/diuresis in these GC-A deficient mice. The proposed studies intend to: 1) determine how the kidney excretes salt in the absence of GC-A; 2) determine if the function of vascular smooth muscle is altered in GC-A deficient mice; 3) determine the consequences of age in mice lacking GC-A; and 4) specifically reverse the effects of the GC-A gene knockout in a tissue-specific manner.
| Lopez, M J; Garbers, D L; Kuhn, M (1997) The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 272:23064-8 |
