1. The candidate: Dr. Cohen will be pursuing a career in academic medicine combining basic research with clinical teaching. During a postdoctoral fellowship in physiology at Yale University under Dr. Gerhard Giebisch he obtained a broad background in the physiology of epithelial transport and extensive experience in electrical techniques useful in studying these transport processes including the patch-clamp method which allows direct recording of single ionic channels. Dr. Cohen worked on developing a suitable preparation for applying this technique to renal epithelia (see appendix) and on microelectrode studies of the basolateral K+ channel in an amphibian proximal tubule. The studies proposed here are a logical continuation of that work. 2. The research: Hepatocytes contain a potassium conductance that responds to Alpha and Beta adrenergic agents as well as a variety of hormones. It is also responsive to intracellular Ca++ and cyclic AMP and these two substances appear to mediate the action of the hormones and neurotransmitters. This conductance is thought to play a role in the translation of the hormonal signals into metabolic events. The conductance is also known to vary directly with transport rate of the Na+ K+ ATPase. This seems to be a property of many epithelial K+ conductances. Preliminary work using the patch-clamp technique has demonstrated the presence of a K+ channel in hepatocytes. In the proposed studies, the calcium sensitivity of the channel will be explored as will the nature of the interaction between calcium and cyclic AMP. The mechanism of coupling between pump and activity will be studied and in particular the hypothesis that altered calcium sensitivity underlies this coupling will be tested. Further studies will explore the interaction between metabolism and the channel, again, with emphasis on modulation of calcium sensitivity. These latter studies are relevant to the question of whether changes in membrane K+ permeability play a role in the pathophysiology of cell damage during anoxia. 3. The environment: Members of the Renal Unit at the Massachusetts General Hospital are actively engaged in several areas of research relevant to this application including the biochemistry of cyclic AMP action. The sponsor, Dr. Alexander Leaf, has been one of the leaders in epithelial transport for many years and in recent years has been focusing his efforts on the consequences of anoxia.
| Cohen, B J; Lechene, C (1990) Alanine stimulation of passive potassium efflux in hepatocytes is independent of Na(+)-K+ pump activity. Am J Physiol 258:C24-9 |
