? During the past funding period a new group of naturally occurring lipids, now known as the phospholipid growth factor (PLGF) family, has been isolated and characterized. We identified and synthesized several novel agonists and antagonists, clarified many of the receptor-mediated effects of PLGFs. PLGFs now emerge as important mediators of cell survival. The original objective continues in the renewal application, but the role in cell survival of PLGFs is the new focus of the investigation. The principal hypothesis of this proposal is that PLGFs through their specific receptors can regulate the survival of intestinal epithelium in response to injury caused by apoptosis-inducing treatments. The two aims for testing this hypothesis are: ? 1. Determine the mechanism by which LPA has antiapoptotic effects in IEC-6 intestinal epithelial cells. ? We will determine the structure-activity relationship among naturally occurring and synthetic lysophosphatidic acid (LPA) analogs to prevent the induction apoptosis after treatment with camptothecin and 7-irradiation, identify which LPA receptor subtypes are capable of mediating protection against apoptosis and determine the effects of LPA on the mitochondrial translocation and expression of Bcl-2-related proteins leading to cytochrome C release and ensuing activation of the caspase-9 --- caspase-3 pathway. ? 2. Optimize the protective effects of orally applied PLGF against radiation-induced apoptotic intestinal epithelial damage in vivo. ? We will determine the localization of LPA receptor subtypes in the villus-crypt unit and establish their role in the antiapoptotic effect using LPA1 and LPA2 receptor knockout mice, determine the pharmacokinetic properties of LPA to optimize the treatment regimen and evaluate the antiapoptotic efficacy amongst the three most effective PLGFs identified in aim 1. ? This is a revised application that has been considerably refocused in its scope. The experiments proposed will pave the way toward the therapeutic development of PLGFs for the treatment of the intestinal side effects of radiation and chemotherapy. These studies will have a twofold impact: first, advance our understanding of the physiological function of PLGF; and, second, provide new information concerning the regulation of apoptosis by G protein-coupled receptors. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Medical Biochemistry Study Section (MEDB)
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Srinivas, Pothur R
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University of Tennessee Health Science Center
Schools of Medicine
United States
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Zhang, Honglu; Xu, Xiaoyu; Gajewiak, Joanna et al. (2009) Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res 69:5441-9
Valentine, William J; Fujiwara, Yuko; Tsukahara, Ryoko et al. (2008) Lysophospholipid signaling: beyond the EDGs. Biochim Biophys Acta 1780:597-605
Fujiwara, Yuko (2008) Cyclic phosphatidic acid - a unique bioactive phospholipid. Biochim Biophys Acta 1781:519-24
Gajewiak, Joanna; Tsukahara, Ryoko; Fujiwara, Yuko et al. (2008) Synthesis, pharmacology, and cell biology of sn-2-aminooxy analogues of lysophosphatidic acid. Org Lett 10:1111-4
Valentine, William J; Fells, James I; Perygin, Donna H et al. (2008) Subtype-specific residues involved in ligand activation of the endothelial differentiation gene family lysophosphatidic acid receptors. J Biol Chem 283:12175-87
Dopico, Alex M; Tigyi, Gabor J (2007) A glance at the structural and functional diversity of membrane lipids. Methods Mol Biol 400:1-13
Gajewiak, Joanna; Tsukahara, Ryoko; Tsukahara, Tamotsu et al. (2007) Alkoxymethylenephosphonate analogues of (Lyso) phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor. ChemMedChem 2:1789-98
Jiang, Guowei; Xu, Yong; Fujiwara, Yuko et al. (2007) Alpha-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. ChemMedChem 2:679-90
Uchiyama, Ayako; Mukai, Mutsuko; Fujiwara, Yuko et al. (2007) Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid. Biochim Biophys Acta 1771:103-12
Pyne, Nigel J; Waters, Catherine M; Long, Jaclyn S et al. (2007) Receptor tyrosine kinase-G-protein coupled receptor complex signaling in mammalian cells. Adv Enzyme Regul 47:271-80

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