Nicole Gibran, MD
Associate Professor, Department of Surgery
Our research efforts explore cell signaling pathways between cutaneous sensory nerve fibers and endothelial cells during response to cutaneous injury. Hypertrophic scars have hypervascularity and increased innervation. In contrast, non-healing ulcers of diabetes mellitus have microangiopathy and decreased innervation. Our long term hypothesis is that following cutaneous injury, (1) sensory nerve fibers secrete neuropeptides such as substance P that regulate endothelial cell response to injury and (2) microvascular endothelial cells secrete neurotrophins that regulate nerve fiber regeneration. These pathways are disrupted in conditions of abnormal wound repair. We will test our hypotheses with the following projects: To determine intracellular mechanisms by which substance P regulates endothelial cell proinflammatory response. We will determine whether the substance P induces endothelial cell production of nerve growth factor, vascular endothelial growth factor and interleukin 8 by (1) G-protein coupled pathways, or (2) cell shape change and cytoskeleton reorganization. To determine the role of nitric oxide synthase in substance P mediated response to injury by endothelial cells. We will determine whether substance P signaling pathways leading to growth factor and cytokine synthesis depend on nitric oxide. To determine which endothelial cell-derived mediators regulate nerve cell sprouting. We will identify endothelial cell-derived neurotrophins that regulate sensory nerve fiber sprouting. To determine the effects of hyperglycemia and matrix glycosylation on microvascular endothelial cells responses. Hyperglycemia directly alters cellular responses and indirectly alters cellular response by extracellular matrix molecule glycosylation. We will determine whether hyperglycemia or matrix molecule glycosylation alter SP-induced endothelial cell mediator synthesis, cytoskeleton organization, and intracellular signaling. 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 alter SP-induced endothelial cell mediator synthesis, cytoskeleton organization, or intracellular signaling. 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 study effects of anti-oxidants, vitamin E, vitamin C and n-acetyl cysteine on cellular responses under hyperlipidemic and hyperglycemic conditions. To determine how neuropeptide activity in transgenic mice and mutant diabetic mice alters response to injury. We will determine how substance P modulates cutaneous response to injury using an excisional wound model in normal mice, diabetic mice and mice with targeted disruption of nitric oxide synthase.