My immediate career objectives are to develop a reputation for high quality research and to train graduate and postdoctoral students in the cardiovascular and lymphatic research field. My long-term career are to advance the level of understanding the regulatory mechanisms of lymphatic muscle contractility under normal and diseased/pathophysiological conditions. Lymphatic muscle exhibits strong/phasic contractions, much higher shortening velocities and different intracellular calcium dynamics. Unfortunately little information is known about the molecular mechanisms that are responsible for these unique characteristics. In this proposal we will use the available contractile protein gene knock out models or transgenic models with overexpression of contractile protein isoforms to test the central hypothesis remodeling of thick or thin filament proteins in the contractile apparatus of lymphatic muscle modulates its contractile dynamics through altering the calcium sensitivity and crossbridge activation mechanisms.
The specific aims are: (1) To determine the functional roles of SM-B myosin heavy chain (MHC) in the phasic and tonic contraction of lymphatics, (2) To define the roles of tropomyosin in the thin filament-mediated contraction of lymphatics. We will use SM-B MHC knockout and SM-MHC/calponin double knockout mouse models. The vascular smooth muscle a-actin promoter will be to express striated muscle tropomyosin in lymphatic muscle. An adenoviral siRNA approach will be used knock down the smooth muscle a- and p-TM gene expression in lymphatics. We will isolated/cannulated vessels from iliac and thoracic duct lymphatics to study the contractile characteristics of lymphatics. Force and calcium measurements will be conducted in the lymphatic segment preparations (both intact and skinned) to determine the calcium sensitivity and cooperativity mechanisms of lymphatics. The contractile mechanisms of lymphatics are poorly understood and this study will significantly advance our knowledge of the basis for the lymphatic vessel function. These studies further advance my training lymphatic research using mouse models, which would allow me to develop and use genomic proteomic approaches to determine the signaling pathways that regulate lymphatic muscle function.
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