Inappropriate responses by vascular smooth muscle to the complex neural and hormonal mechanisms governing contraction or to growth factors governing growth and replication occur in most cases of morbidity and mortality in the United States. Hypertension and vasospasm are example of failures of regulation of contraction, while atherosclerosis and post-angioplasty restenosis reflect inappropriate growth responses. Therapy frequently targets critical steps in the signal transduction events linking receptors in the vascular cell membranes to intracellular second messengers and allosteric or covalent regulatory mechanisms that govern the biological activity of cellular proteins or genetic material. The broad objective of the program is to identify the signals and determine the signal transduction events that regulate contraction, growth and replication of smooth muscle. The approaches are largely molecular, but represent the disciplines of biochemistry, biophysics, and cell biology. The unifying focus in the program are the signaling cascades in smooth muscle induced by agonist-receptor complex formation. These signaling cascades include those involved in modulation of the Ca++-sensitivity of contraction, regulation of crossbridge phosphorylation, and ribosomal gene transcription. All these signaling cascades have common initiation events before diverging while presumably exhibiting some degree of cross-talk. Comparable cross-talk occurs between each project as a result of formal collaborations and common signal transduction events.
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