Mucosal healing requires epithelial motility, proliferation, and differentiation. Focal adhesion kinase (FAK) influences all three. FAK is an autophosphorylating tyrosine kinase that mediates downstream signals by receptors for matrix proteins and many growth factors and may promote epithelial cell motility, a critical first step in mucosal healing. Most studies have focused on FAK activation within minutes after ligand binding to FAK-associated membrane receptors. However, our preliminary studies suggest that FAK may be regulated at the protein level as well as in its phosphorylation during gut epithelial cell motility in vitro and during mucosal healing in vivo. This grant will focus on the exploration of the regulation of FAK protein levels, about which little is known. We hypothesize that integrin- and FAK- related signal events regulate FAK protein pools at the mRNA level, by modulating FAK gene transcription or FAK mRNA degradation, and that TGFbeta stimulates FAK by acting on this pathway. We now propose to demonstrate that FAK protein changes are biologically significant, identify the key control points for regulation of intracellular FAK protein and mRNA pools during intestinal epithelial motility, and determine how TGFbeta regulates FAK protein and mRNA in migrating intestinal epithelial cells and what signals mediate these effects. We will validate our in vitro observations in a murine Smad 3 knockout mouse model and in tissue from human mucosal wounds, including peptic ulcers and inflammatory bowel disease. We expect to demonstrate the importance of protein levels of this critical molecule in gut epithelial wound healing and to define the mechanisms that regulate its synthesis. These results will characterize a previously unknown pathway by which intestinal epithelial cell motility is regulated and its specific modulation by TGFbeta. We can then, in the future, study how this pathway goes awry in instances of defective mucosal healing and target pharmacologic interventions to improve mucosal healing. Furthermore, although different cells may exhibit different patterns of FAK regulation, this work will also provide a paradigm by which FAK protein regulation can be studied in other cells and settings, where FAK may be involved in processes as diverse as malignant transformation and atherogenesis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Hamilton, Frank A
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Michigan State University
Schools of Medicine
East Lansing
United States
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Kovalenko, Pavlo L; Basson, Marc D (2013) The correlation between the expression of differentiation markers in rat small intestinal mucosa and the transcript levels of schlafen 3. JAMA Surg 148:1013-9
Kovalenko, Pavlo L; Kunovska, Lyudmyla; Chen, Jian et al. (2012) Loss of MLK3 signaling impedes ulcer healing by modulating MAPK signaling in mouse intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 303:G951-60
Kovalenko, Pavlo L; Basson, Marc D (2012) Changes in morphology and function in small intestinal mucosa after Roux-en-Y surgery in a rat model. J Surg Res 177:63-9
Kovalenko, Pavlo L; Flanigan, Thomas L; Chaturvedi, Lakshmi et al. (2012) Influence of defunctionalization and mechanical forces on intestinal epithelial wound healing. Am J Physiol Gastrointest Liver Physiol 303:G1134-43
Chaturvedi, Lakshmi S; Zhang, Ping; Basson, Marc D (2012) Effects of extracellular pressure and alcohol on the microglial response to inflammatory stimulation. Am J Surg 204:602-6
Yuan, Lisi; Sanders, Matthew A; Basson, Marc D (2011) ILK mediates the effects of strain on intestinal epithelial wound closure. Am J Physiol Cell Physiol 300:C356-67
Chaturvedi, Lakshmi S; Marsh, Harold M; Basson, Marc D (2011) Role of RhoA and its effectors ROCK and mDia1 in the modulation of deformation-induced FAK, ERK, p38, and MLC motogenic signals in human Caco-2 intestinal epithelial cells. Am J Physiol Cell Physiol 301:C1224-38
Gayer, Christopher P; Craig, David H; Flanigan, Thomas L et al. (2010) ERK regulates strain-induced migration and proliferation from different subcellular locations. J Cell Biochem 109:711-25
Opreanu, Razvan C; Kuhn, Donald; Basson, Marc D (2010) Influence of alcohol on mortality in traumatic brain injury. J Am Coll Surg 210:997-1007
Sanders, Matthew A; Ampasala, Dinakar; Basson, Marc D (2009) DOCK5 and DOCK1 regulate Caco-2 intestinal epithelial cell spreading and migration on collagen IV. J Biol Chem 284:27-35

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