? This proposal explores cell signaling pathways that occur between cutaneous sensory nerve fibers and endothelial cells in response to cutaneous injury. Our previous data suggest that nerve-derived neuropeptides contribute to the normal wound repair process. In contrast, non-healing chronic ulcers associated with diabetes mellitus are characterized by microangiopathy and decreased innervations. Based on encouraging data during the past funding period we continue to explore our hypothesis that in patients with diabetes mellitus, hyperglycemia and hyperlipidemia impair microvascular endothelial cell response to nerve-derived neuropeptides and endothelial cell production of necessary inflammatory mediators. These abnormalities contribute to impaired response to cutaneous injury. We will test our hypothesis by addressing the following Aims:
Aim 1 : To determine the effects of hyperglycemia and matrix glycosylation on microvascular endothelial cells responses. Hyperglycemia can directly alter cellular responses and can indirectly alter cellular response by extracellular matrix molecule glycosylation. We will determine whether hyperglycemia and/or matrix molecule glycosylation alters SP-induced endothelial cell mediator synthesis, cytoskeleton organization, integrin expression and intracellular signaling.
Aim 2 : To determine the effect of elevated fatty acid levels on endothelial cell responses. Hyperlipidemia is strongly associated with complications in diabetes mellitus. We will determine whether elevated fatty acids alone or as Triglycerides alter SP-induced endothelial cell mediator synthesis, cytoskeleton organization, integrin expression or intracellular signaling.
Aim 3 : To determine the anti-oxidant regulation of microvascular endothelial cell response to hyperglycemia & hyperlipidemia. Oxidative stress due to hyperlipidemia may alter cellular response to injury. We will continue our studies of effects of antioxidants, vitamin E, vitamin C and n-acetyl cysteine on cellular responses under hyperlipidemic and hyperglycemic conditions.
Aim 4 : To determine whether restoration of neuropeptide activity improves wound repair in diabetic mice. We will use several approaches to evaluate the roles of neuropeptides in wound repair. Using an excisional wound repair model in hyperglycemic db/db mice, we will replace substance P and inhibit neutral endopeptidases activity. We will also test the effects of antioxidants in this murine wound model. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-W (03))
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Jones, Teresa L Z
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University of Washington
Schools of Medicine
United States
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Wang, Qiang; Muffley, Lara A; Hall, Kyla et al. (2009) Elevated glucose and fatty acid levels impair substance P-induced dermal microvascular endothelial cell migration and proliferation in an agarose gel model system. Shock 32:491-7
Muangman, Pornprom; Tamura, Richard N; Muffley, Lara A et al. (2009) Substance P enhances wound closure in nitric oxide synthase knockout mice. J Surg Res 153:201-9
Scott, Jeffrey R; Tamura, Richard N; Muangman, Pornprom et al. (2008) Topical substance P increases inflammatory cell density in genetically diabetic murine wounds. Wound Repair Regen 16:529-33
Sullivan, Stephen R; Underwood, Robert A; Sigle, Randall O et al. (2007) Topical application of laminin-332 to diabetic mouse wounds. J Dermatol Sci 48:177-88
Muangman, Pornprom; Tamura, Richard N; Gibran, Nicole S (2005) Antioxidants inhibit fatty acid and glucose-mediated induction of neutral endopeptidase gene expression in human microvascular endothelial cells. J Am Coll Surg 200:208-15
Sullivan, Stephen R; Underwood, Robert A; Gibran, Nicole S et al. (2004) Validation of a model for the study of multiple wounds in the diabetic mouse (db/db). Plast Reconstr Surg 113:953-60
Muangman, Pornprom; Muffley, Lara A; Anthony, Joanne P et al. (2004) Nerve growth factor accelerates wound healing in diabetic mice. Wound Repair Regen 12:44-52
Muangman, Pornprom; Spenny, Michelle L; Tamura, Richard N et al. (2003) Fatty acids and glucose increase neutral endopeptidase activity in human microvascular endothelial cells. Shock 19:508-12
Gibran, Nicole S; Tamura, Richard; Tsou, Ray et al. (2003) Human dermal microvascular endothelial cells produce nerve growth factor: implications for wound repair. Shock 19:127-30
Spenny, Michelle L; Muangman, Pornprom; Sullivan, Stephen R et al. (2002) Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen 10:295-301