Geriatric, malnourished, and diabetic patients with vascular insufficiencies are at increased risk for the development of non-healing dermal wounds that are associated with high morbidity and sometimes mortality. The objectives of the application are to acquire new skills and knowledge investigating dermal wound healing processes, to gain experience in teaching others, and to achieve the necessary expertise to lead an independent research group. These experiences and training at Brigham and Womens Hospital/Harvard Medical School will incorporate the participation in several structured and research activities ultimately leading to scientific independence. The laboratory encompasses 2,500 square feet of newly renovated space equipped with instruments designed for research in cellular and molecular biology, protein chemistry, animal physiology, and histology. The proposed research will examine the role of an extracellular matrix protein, ACLP (aortic carboxypeptidase-like protein) in dermal wound healing. They generated ACLP-null mice, which spontaneously develop non-healing skin ulcers. They hypothesize that an absence of ACLP may prevent healing of skin wounds by impairing the proliferation, differentiation, or migration of dermal fibroblasts.
In Aim 1, they will determine the mechanisms by which an absence of ACLP leads to poor wound healing using histological analysis and in vitro assays.
In Aim 2, they will identify specific DNA sequences and transcription factors important for regulating the expression of ACLP in dermeal fibroblasts in vitro using reporter gene assays. ACLP promoter LacZ reporter transgenic mice will be generated to evaluate the transcriptional regulation of ACLP during dermal wound healing in vivo.
In Aim 3, they will investigate the biological function of ACLP and its interaction with other extracellular matrix proteins and discoidin domain receptor tyrosine kinases (DDR). A series of ACLP and DDR-deletion mutants will be generated to identify domains important for these interactions. In addition, gain-of-function experiments using recombinant adenovirus that produces ACLP will be performed.
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