Lysophosphatidic acid (LPA) is known to regulate wound healing in many physiological and pathophysiological states. LPA receptors (LPARs) are widely distributed and play a critical role in regulating a multitude of functions related to growth, differentiation, and cytoskeletal responses. Nevertheless, their role in regulating oral wound healing is not known. We have recently provided the first evidence that: 1) LPA stimulates human gingival (GF) and periodontal ligament fibroblast (PDLF) migration and proliferation; 2) LPA positively regulates their responses to platelet-derived growth factor (PDGF); and 3) GF and PDLF have mRNA for all three subtypes (LPA1-3) of LPARs. This application is designed to lead to an understanding of the mechanisms of action used by LPARs in GF and PDLF. We will begin to identify the downstream effector molecules involved in order to determine their respective roles in controlling the fibroblasts migration and growth. The hypothesis is that the LPARs on oral fibroblasts regulate key molecular signaling mechanisms controlling their mitogenic and migration responses, and their responses to PDGF. Our three Specific Aims propose to: 1) Test the hypothesis that LPA2 will be involved in the mitogenic response, and LPA1 and LPA2 in the migration response by knocking down LPAR mRNA with antisense oligonucleotides to test which receptor(s) are involved. 2) Test the hypothesis that the phosphoinositide pathway in GF and PDLF is involved in regulating the mitogenic and migration responses by using antibodies (abs) to protein kinase C and biochemical activator/inhibitor studies. 3) Test the hypothesis that LPA transactivates the PDGF receptor (PDGFR) and increases cellular expression of the PDGFR by using activation-state-specific abs to the PDGFR and radioligand binding studies. These studies will provide knowledge that will be essential to using LPA agonists in delivery systems to speed periodontal wound healing. This would be especially valuable in patients with various metabolic conditions and diseases like diabetes, where using the patient platelet-rich plasma is less than ideal as a regenerative therapy. ? ?
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| George, Joju; Headen, Karmel V; Ogunleye, Afolabi O et al. (2009) Lysophosphatidic Acid signals through specific lysophosphatidic Acid receptor subtypes to control key regenerative responses of human gingival and periodontal ligament fibroblasts. J Periodontol 80:1338-47 |
| Cerutis, D Roselyn; Dreyer, Andrew C; Vierra, Matthew J et al. (2007) Lysophosphatidic acid modulates the healing responses of human periodontal ligament fibroblasts and enhances the actions of platelet-derived growth factor. J Periodontol 78:1136-45 |
