It is apparent that MARCKS protein is a major signaling molecule in a variety of cellular functions. In the ung, MARCKS serves as a crossbridge between stimulation at the cell surface and subsequent secretion of mucin from epithelial secretory cells. MARCKS also can serve as a mediator of leukocyte degranulation as well as leukocyte migration, suggesting it also has an important role in inflammation. One of the key findings of the previous funding period is that it appears to be the N-terminus of MARCKS that is involved in these functions, as a peptide identical to the MARCKS N-terminus has potent effects on these parameters when cells are treated with it. The studies in the next funding period will now investigate and further nail down the exact molecular mechanism(s) by which MARCKS interacts with other cellular proteins in each of these cell types in order to carry out its function. We will use some new imaging techniques as well as develop new methods to assay for secretion and epithelial function. We plan to use proteomic approaches to identify novel proteins associated with mucin granule membranes and investigate their interactions with MARCKS during the secretory process. We also plan to expand our collaborations with investigators at Duke Medical enter to move into translational studies utilizing airway epithelial cells derived from patients with asthma, COPD and CF and the role(s) of MARCKS in secretion by these individuals. In addition, we anticipate moving to several in vivo models of mucus hypersecretion, airway inflammation and cell migration to show that these mechanisms are operative in vivo and thus could represent some important new therapeutic targets. Relatedly, the aims of the next period are: I. Determine the specific protein-protein interactions that influence MARCKS protein function in mucin secretion in vitro and in vivo. II. Determine the role of MARCKS in neutrophil migration and inflammation. III. Initiate translational studies utilizing human cells from donors with asthma and COPD, with and without viral infections.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Banks-Schlegel, Susan P
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North Carolina State University Raleigh
Anatomy/Cell Biology
Schools of Veterinary Medicine
United States
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Sheats, Mary K; Pescosolido, Kimberly C; Hefner, Ethan M et al. (2014) Myristoylated Alanine Rich C Kinase Substrate (MARCKS) is essential to ?2-integrin dependent responses of equine neutrophils. Vet Immunol Immunopathol 160:167-76
Chen, C-H; Thai, P; Yoneda, K et al. (2014) A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis. Oncogene 33:3696-706
Li, Jingjing; D'Annibale-Tolhurst, Melissa A; Adler, Kenneth B et al. (2013) A myristoylated alanine-rich C kinase substrate-related peptide suppresses cytokine mRNA and protein expression in LPS-activated canine neutrophils. Am J Respir Cell Mol Biol 48:314-21
Fang, Shijing; Crews, Anne L; Chen, Wei et al. (2013) MARCKS and HSP70 interactions regulate mucin secretion by human airway epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 304:L511-8
Raiford, Kimberly L; Park, Joungjoa; Lin, Ko-Wei et al. (2011) Mucin granule-associated proteins in human bronchial epithelial cells: the airway goblet cell "granulome". Respir Res 12:118
Seibold, Max A; Wise, Anastasia L; Speer, Marcy C et al. (2011) A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 364:1503-12
Green, Teresa D; Crews, Anne L; Park, Joungjoa et al. (2011) Regulation of mucin secretion and inflammation in asthma: a role for MARCKS protein? Biochim Biophys Acta 1810:1110-3
Eckert, Rachael E; Neuder, Laura E; Park, Joungjoa et al. (2010) Myristoylated alanine-rich C-kinase substrate (MARCKS) protein regulation of human neutrophil migration. Am J Respir Cell Mol Biol 42:586-94
Foster, W Michael; Adler, Kenneth B; Crews, Anne L et al. (2010) MARCKS-related peptide modulates in vivo the secretion of airway Muc5ac. Am J Physiol Lung Cell Mol Physiol 299:L345-52
Miller, Jeffrey D; Lankford, Susan M; Adler, Kenneth B et al. (2010) Mesenchymal stem cells require MARCKS protein for directed chemotaxis in vitro. Am J Respir Cell Mol Biol 43:253-8

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