The unifying hypothesis of this proposal is that macromolecular complex of type 2 lysophosphatidic acid receptor (LPA2 receptor) and Na+/H+ exchange regulatory factor-2 (NHERF2) plays important roles in the pathogenic process of secretory diarrhea.
We aim to study the formation and regulation of the macromolecular complex at the molecular level under physiological and pathophysiological conditions that play a critical role in cholera induced diarrhea. Moreover, the research will study the mechanism through which LPA2 receptor- mediated signaling events regulate CFTR-dependent electrolyte secretion in cells and fluid secretion in an animal model of diarrhea.
Three aims will be studied:
Aim 1 : To test the hypothesis that LPA2 receptor is primarily expressed on the luminal surface of the gut and is down regulated in certain forms of diarrheal diseases, and to test the hypothesis that activation of LPA2 receptor inhibits compartmentalized cAMP generation at the plasma membrane.
Aim 2 : To test the hypothesis that LPA can regulate the formation of the LPA2-containing macromolecular complex by further clustering it to microdomain on the plasma membrane and that the process is mediated by NHERF2-dependent protein-protein interactions Aim 3: To test the hypothesis that disruption of the macromolecular complex by silencing NHERF2 alters compartmentalized cAMP levels at the plasma membrane and that in vivo NHERF2 knockout mice generate altered cAMP in response to CTX. The proposal is of great importance and significance for understanding the pathogenic process of the deadly secretory diarrheal diseases at the molecular level, and for possible therapeutic intervention of the disease. The proposed study is highly innovative in both conceptual advance and in technology/technique development.

Public Health Relevance

In this study we propose that the macromolecular complex of LPA2 and NHERF2 is regulated by LPA signaling, which further clusters the macromolecular complex to subdomain on the plasma membrane, and that the macromolecular complex plays important role in regulating compartmentalized cAMP level in proximity to CFTR channel, thus regulating CFTR-dependent electrolyte and fluid secretion in gut epithelial cells and in the mouse model. Therefore, the macromolecular complex plays an important role in pathogenic process of secretory diarrhea. By targeting the macromolecular complex, we may find ways to control fluid secretion and thereby control or cure the diarrheal disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Grey, Michael J
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University of Tennessee Health Science Center
Schools of Medicine
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Zhang, W; Zhang, X; Zhang, Y H et al. (2016) Lumacaftor/ivacaftor combination for cystic fibrosis patients homozygous for Phe508del-CFTR. Drugs Today (Barc) 52:229-37
Moon, Changsuk; Zhang, Weiqiang; Ren, Aixia et al. (2015) Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea. J Biol Chem 290:11246-57
Lin, Sui; Ikegami, Machiko; Moon, Changsuk et al. (2015) Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) Specifically Interacts with Phospholipid Transfer Protein StarD10 to Facilitate Surfactant Phospholipid Trafficking in Alveolar Type II Cells. J Biol Chem 290:18559-74
Arora, Kavisha; Sinha, Chandrima; Zhang, Weiqiang et al. (2015) Altered cGMP dynamics at the plasma membrane contribute to diarrhea in ulcerative colitis. Am J Pathol 185:2790-804
Sinha, Chandrima; Zhang, Weiqiang; Moon, Chang Suk et al. (2015) Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry. Chembiochem 16:2017-22
Moon, Changsuk; Zhang, Weiqiang; Sundaram, Nambirajan et al. (2015) Drug-induced secretory diarrhea: A role for CFTR. Pharmacol Res 102:107-12
Sinha, Chandrima; Ren, Aixia; Arora, Kavisha et al. (2015) PKA and actin play critical roles as downstream effectors in MRP4-mediated regulation of fibroblast migration. Cell Signal 27:1345-55
Holcomb, Joshua; Jiang, Yuanyuan; Lu, Guorong et al. (2014) Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Biochem Biophys Res Commun 446:399-403
Ren, Aixia; Moon, Changsuk; Zhang, Weiqiang et al. (2014) Asymmetrical macromolecular complex formation of lysophosphatidic acid receptor 2 (LPA2) mediates gradient sensing in fibroblasts. J Biol Chem 289:35757-69
Sinha, Chandrima; Arora, Kavisha; Moon, Chang Suk et al. (2014) Förster resonance energy transfer - an approach to visualize the spatiotemporal regulation of macromolecular complex formation and compartmentalized cell signaling. Biochim Biophys Acta 1840:3067-72

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