Role of Polarity Complex Signaling on Non-muscle Myosin in Intestinal Epithelia

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DESCRIPTION (provided by applicant): Our laboratory recently reported that the "polarity complex" (atypical PKC-Par3-Par6), an evolutionarily conserved signaling pathway is deeply downregulated under inflammatory TNF signaling. It is also downregulated in a mouse model of colitis as well as in ulcerative colitis and Crohn's disease patients. Because Inflammatory Bowel Disease represents a substantial problem for human health, I would like to further analyze the downstream consequences of aPKC downregulation. Our published and preliminary data show that the polarity complex exerts antagonistic control on the activation of non-muscle Myosin IIA, a broadly accepted effector of inflammatory signaling in epithelial cells. Other laboratories have shown the involvement of nmMyosin II in tight junction maintenance and downstream of inflammatory signaling, but we are the first to postulate specifically one of the isoforms nmMyoIIA as the main molecular mechanism controlling epithelial barrier. Accordingly, here I put forth the hypothesis that: Inflammation-dependent downregulation of the polarity complex aPKC is a novel signaling mechanism that synergistically upregulates the apical expression of nmMyosinIIA abrogating direct phosphorylation of the heavy chains. This project is devoted to analyze the effects and the molecular mechanisms by which aPKC-Par3-Par6 antagonizes MLCK- mediated nmMyosin II activation. PUBLIC HEALTH RELEVANCE: Inflammation in various organs and systems is responsible for a vast array of human disease. In the intestine, in particular, inflammation is the result o an imbalance of the immune system response to the luminal microbiota. As a result, Inflammatory Bowel Disease is a multifactorial aberrant response of the immune system that, among other effects, impacts on the layer of cells lining the intestinal lumen, the epitheliu. It is estimated that nearly 2 million Americans are affected, presenting two possible forms of the disease, ulcerative colitis or Crohn's disease. The economic impact of this disease is very important as in other chronic conditions. Currently, the treatment options are restricted and relapse is common. This project studies a novel intracellular signaling pathway in the epithelium that complements and synergizes with the commonly accepted pathway. The role of a specific protein (non-muscle myosin IIA) in controlling the permeability of the intestinal barrier under such signaling stimuli will be analyzed.