The neuroendocrine and immune systems communicate bi-directionally and this is mediated in part through neuropeptide hormones and cytokines. One of the most interesting yet least understood aspects of this communication is that leukocytes can synthesize neuropeptide hormones. While the production is reproducible and well documented, the fundamental role of leukocyte-derived neuropeptides is not known. The significance of leukocyte production of neuropeptides has been difficult to assess, in part because in vivo they are produced in the context of the neuroendocrine system and its much larger contribution of neuropeptide. One of these leukocyte-derived neuropeptides, corticotropin releasing factor (CRF) is a particularly interesting regulator that has many effects on neuroendocrine and immune responses and may be a key regulator between these systems. Studies have shown that CRF may suppress or enhance selected immune responses. Our hypothesis is that leukocyte production of CRF modulates inflammation, at least at the local site through specific receptors. This is an exploratory/developmental proposal to develop a mouse model in which the leukocytes are the sole source of CRF. This could then be used to determine what the role of leukocyte-derived CRF may be in vivo. It could also serve as a model to study other leukocyte-derived neuropeptides in future studies. Specifically we aim to: 1) To identify and localize CRF production and CRF receptor subtypes in an in vivo model of inflammation and antibody production. 2) To develop a chimeric mouse in which only the leukocytes produce CRF and to test the ability of leukocyte CRF production to modulate an inflammatory process. This project should show the importance of CRF in an inflammatory response. There is experimental evidence to suggest that CRF is involved in several inflammatory diseases of humans including arthritis, asthma, and inflammatory bowel diseases plus it could possibly play a role in multiple sclerosis. New CRF receptor antagonists are being developed and once understood might be useful in therapies that could be directed at the infiltrating leukocytes at the sites of inflammation in these diseases. This project's goal is to determine the importance of a neuropeptide, corticotropin releasing factor in inflammation. Inflammatory diseases are a major cause of illness and death and understanding the regulation of inflammation should allow the development of targeted and powerful new treatments for these diseases. ? ? ? ?
