9728881 HALVORSEN The secreted, biologically active molecules called cytokines play key roles in the differentiation and maturation of a variety of tissues during embryonic development. It is important to determine the molecular mechanisms for these cytokine actions for a general understanding of nervous system development. The recently described "neuropoietic" cytokines have potential roles in the developing nervous and cardiovascular systems which are, as yet, largely undefined. The overall goal of this study is to understand the functional role of the cytokine ciliary neurotrophic factor (CNTF) in development of the heart and its innervation. The mechanisms important for expression of CNTF receptors during development will be investigated, the molecular mechanisms that regulate these receptors in heart tissue and in cultured myocytes during parasympathetic synapse formation will be defined, and the effects of CNTF on key synaptic components will be identified in the heart. Upon completion of the project three fundamental questions will have been addressed. (1) Does the change in CNTF receptor levels result in changes in tissue CNTF sensitivity? (2) What is (are) the mechanism(s) of regulation of CNTF receptors in heart? (3) Does CNTF play a role in parasympathetic synapse formation in the developing atria? Over the long term, downstream gene and biochemical targets of CNTF and related cytokine action in heart will be determined. These studies represent some of the first to define the expression and function of CNTF receptors in the cardiovascular system. With this new information we will have a better understanding of the mechanisms that regulate nerve-heart cell responses to cytokines during embryonic development and of mechanisms that may be important for maintenance of these functions in the adult.
