With increased patient survival following large burn injuries, disability due to hypertrophic scar formation has become an important clinical problem that affects as many as 100,000 patients per year in the United States. This abnormal response to wound repair results in significant patient misery due to both the unsightly deformity and also devastating itching and pain. The scars are characterized by abnormal hypervascularity and increased innervation. This proposal presents a novel concept that cell signaling occurs between cutaneous sensory nerve fibers and endothelial cells during wound repair processes. Our hypothesis has two limbs: 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. We anticipate that increased endothelial cell proliferation and neurotrophin synthesis may lead to the clinical findings of hypervascularity and pruritis seen in hypertrophic scars. We will test our hypothesis by addressing the following aims:
Specific Aim 1 : To determine the mechanism by which substance P regulates endothelial cell release of neurotrophins. We will determine whether the neuropeptide substance P directly regulates endothelial cell transcription of neurotrophins or whether the changes in endothelial cell shape and cytoskeletal organization induced by substance P increase neurotrophin release.
Specific Aim 2 : To determine the mechanism by which extracellular matrix - integrin interactions regulate neurotrophin secretion. We will determine whether changes in endothelial cell shape and cytoskeleton reorganization due to integrin aggregation alone regulate neurotrophin production in vitro or whether neurotrophin production is independent of changes in cell shape.
Specific Aim 3 : To determine which endothelial cell-derived neurotrophins regulate nerve cell sprouting. We will determine which endothelial cell-derived neurotrophins regulate sensory nerve fiber differentiation and sprouting in vitro.
Specific Aim 4 : To determine whether interruption of either neuropeptide or neurotrophin activity in transgenic mice alters the response to injury. We will use an excisional wound model in mice with targeted disruption of the substance P receptor (neuropeptide activity) or the nerve growth factor receptor (neurotrophin activity.) to determine the consequences of targeted deletions on capillary and nerve regeneration in wounds.
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