Adrenergic receptors (AR) are cell surface proteins that are the receptors for the endogenous catecholamines epinephrine and norepinephrine. These receptors are widely distributed throughout the cardiovascular and pulmonary systems and subserve a number of key functions, including modulation of cardiac inotropy and chronotropy, systemic vascular resistance, and bronchial smooth muscle tone. Adrenergic receptors are the targets for many drugs which act as agonists or antagonists ina the treatment of diseases such as hemodynamic shock, congestive heart failure, angina, hypertension, asthma. The focus of this proposal is on the betaARclass (composed of Beta1AR, beta2AR, and beta3AR subtypes) and the alpha2AR (composed of the alpha2C10, alpha2C4, and alpha2C2 subtypes) which have opposites effects on the effector enzyme adenylyl cyclase. With site- directed mutagenesis and recombinant expression studies, we now know many of the structural determinants required for certain properties of these receptors. However, their relevance within the context of heart and lung function in normal or diseased states is not known. Thus one objective of this research is to develop and study mice expressing mutated adrenergic receptors which lack single components of the transduction process. We have also recently found that the beta2AR is highly polymorphic in the normal population, and some polymorphisms are overrepresented in cohorts of patients with asthma and congestive heart failure. in some cases the polymorphisms which result in changes in the encoded amino acid significantly alter receptor function as assessed in in vitro recombinant expression systems. However, the physiologic significance of such polymorphisms for heart and lung function is not known. Thus the second objective is to develop and study mice expressing the known polymorphic forms of the beta1AR and beta2AR in heart and lung. In both Aims 1 and 2, a gene replacement strategy will be utilized to eliminate the background of endogenous wild-type receptor and to maintain physiologic levels of receptor expression. The third objective relates to mechanisms which are involved in the expression of the adrenergic receptors. Despite their importance in heart and lung function, little is known about how expression is regulated or what factors are critical for tissue specific expression. Thus this third objective will be to delineate critical regions of the genes for these receptors which are important for expression and to determine the transcription factors involved in cell-type specific expression.
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