Small bowel transplantation (SBT) is the new frontier in organ transplantation. However, very little is known about enteric function of the transplanted (extrinsically denervated) gut. This is important because SBT leads to marked enteric motor and absorptive dysfunction. Most previous work has centered on the immunobiology of gut transplantation. This proposal, as our last 14 years of consecutive NIH funding, addresses specifically the enteric physiology of the transplanted (extrinsically denervated) gut. The overall aim continues to be to understand the mechanisms of enteric function (and dysfunction) of the transplanted gut. Based on our previous work, our overall hypothesis is that extrinsic denervation contributes significantly to motor and absorptive enteric dysfunction that is both region and time-dependent and influenced by compensatory enteric neuromuscular and neuroepithelial """"""""adaptation"""""""" (adaptive mechanisms). The proposal is divided into 2 parts--Part A: Motility and Part B: Absorption. What is new about this proposal is that it builds on our past work to expand into new state-of-the-art techniques to define neuromuscular mechanisms coordinating contractile activity of circular and longitudinal gut muscle and neural control of gene expression and function of sugar transport proteins (an unexplored field). We will use an in vivo, integrative hypothesis-driven approach to study physiologic mechanisms in the whole animal using specific, novel surgical models of transplantation (dog, rat, mouse) as well as directed in vitro and molecular approaches to study neuromuscular and neuroepithelial mechanisms (smooth muscle contractile activity, solute transport protein expression and function).
The specific aims i nclude: A: To define mechanisms which alter inhibitory and excitatory neural input to gut smooth muscle early after extrinsic denervation and to determine how adaptive mechanisms of neuromuscular coordination compensate to reverse or counterbalance these acute changes. B: To define molecular mechanisms by which extrinsic innervation regulates solute and water transport in the small intestine.
These specific aims move on to new fields from our past work. This proposal will define important, novel neural mechanisms regulating motor and absorptive function in the denervated gut. Selected aspects have translational value to clinical gut transplantation. ? ?
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