Does Nitric Oxide Regulate Pancreatic Secretion?

Project Overview

This project proposes to examine whether the recently discovered signaling molecule, nitric oxide (NO), contributes to the regulation of pancreatic secretion. The millions of cells that make up the pancreas must produce a coordinated response after stimulation by a diffuse hormonal signal from the small intestine. These hormones cause the pancreas to secrete digestive enzymes. Individual pancreatic cells vary widely in their response to intestinal hormones, yet the assembled tissue exhibits a very coordinated and uniform response to the hormones. The difference between the response of individual cells and the tissue suggests that the hormones may initiate the production of a secondary signal to coordinate the tissue into a uniform response. This type of tissue coordination has not been previously investigated. Nitric oxide has characteristics that make it an ideal candidate. Importantly, nitric oxide crosses cell membranes and can therefore be transferred between neighboring cells to foster coordination. Therefore, using techniques and procedures available in my faculty sponsor's lab, I will determine whether hormone stimulation of the pancreas results in NO production, whether direct application of NO is sufficient to initiate pancreatic secretion in the absence of hormone, and I will work to identify the biochemical target of NO. It is my desire to eventually gain a Ph.D. and to focus my career in the area of cancer research. Cancer is characterized by the disruption of cellular communication and its study utilizes many of the same skills and techniques. I hope that the experience I gain as an undergraduate researcher will therefore accelerate my scientific education and enhance my career potential.

Project Description

Introduction: Funds are requested to support laboratory research in cell biology. The proposed project will test the hypothesis that nitric oxide (NO) is produced by the pancreas in response to hormonal stimulation and that NO serves to promote and coordinate secretion throughout the pancreatic tissue. NO began to be recognized as an important regulator of blood pressure in the early 1990s. Since then, NO has been the subject of over 30,000 scientific papers. Therefore, a great deal is known about its mechanism of production (Stamler et al., 1992) and its distribution (Titheradge, 1998). The vast majority of the functional studies have focused on three areas; 1) regulation of blood pressure through NO influence on vascular smooth muscle; 2) immune cell function; and 3) apoptosis or programmed cell death important to development and control of cancer cells. However, the broad production of NO throughout the body, coupled to the local nature of its activity, suggests that this novel signaling molecule may have a fundamental influence on cell physiology and be a more general signaling molecule than initially assumed. Therefore, the more basic aim of this project will be to use the pancreas as a model system to demonstrate that NO influences virtually all cells through an interaction with a common component of cell physiology, and that the subsequent response is then tissue specific. This tissue specific premise has been demonstrated for other types of signaling systems. For example, calcium is a common signal in virtually all cells and changes in its concentration causes the type of tissue specific responses alluded to above. An increase in calcium in muscle causes contraction, in nerves it causes release of neurotransmitter, in the stomach it causes release of gastric acid, and in the kidney it causes concentration of urine. This project will approach the role of NO in an analogous fashion whereby NO may cause relaxation in vascular muscle, or antibody production in immune cells, or apoptosis in canc