Chronic skin wounds in the diabetic patient population are a major health problem for the Nation and the VA. Only one biologic, PDGF-BB (becaplermin Gel), is approved by the Federal Drug Administration (FDA) to treat diabetic lower limb skin wounds. However, the modest efficacy and expense of this product have limited its use in the clinic. During the last VA grant cycle, we have identified the extracellular form of heat shock protein 90alpha (Hsp90?) as an agent that promotes the cellular migration of human keratinocytes, human dermal fibroblasts and human microvascular endothelial cells, the very cells involved in skin wound healing. Moreover, Hsp90? (and its smaller F-5 fragment) when added topically to skin wounds of normal and diabetic mice dramatically accelerates the wound closure. Our hypothesis is that Hsp90? accelerates the closure of skin wounds by promoting migration of keratinocytes (for re-epithelialization), dermal fibroblasts (for fibroplasia) and microvascular endothelial cells (for no-vascularization). No single conventional growth factor is able to do the same. In this proposal, we wish to test the efficacy of recombinant Hsp90? and F-5 to accelerate wound closure in normal and diabetic pigs, the animal species whose skin is biologically the closest to human skin. We will evaluate the rate of wound closure, the quality of the healed wounds with regard to scarring and any degree of """"""""regenerative"""""""" (rather than """"""""reparative"""""""") wound healing. Secondly, we will explore the mechanisms by which diabetes inhibits the closure of skin wounds and determine how topically administered Hsp90? rescues the basic biological perturbation in diabetic skin wounds, as we previously reported in db/db mice. With these mechanistic studies paired with our porcine in vivo wound healing data, we will be poised to advance this potential agent for preparation of an investigational new drug (IND) application to the FDA and human clinical trials.
Fifteen percent of elderly adults in the US suffer from chronic skin wounds generating $18 billion per year in healthcare costs. Diabetic wounds, pressure ulcers, and leg ulcers are very common problems in our Veteran population. The administration of growth factors to heal chronic wounds has largely failed. During the last VA funding cycle, we discovered that the secreted form of heat shock protein-90alpha (Hsp90) promotes the migration of keratinocytes, dermal fibroblasts, and microvascular endothelial cells (the three salient cells needed to heal a skin wound) and dramatically accelerates the closure of acute and diabetic skin wounds in animals. In this proposal, we will establish a preclinical porcine model and the mechanistic data necessary for an investigational new drug (IND) application to the FDA and advance the translation of Hsp90 for use in patients, particularly our Veteran patients who suffer greatly from diabetic and chronic skin wounds.
|Zou, M; Bhatia, A; Dong, H et al. (2017) Evolutionarily conserved dual lysine motif determines the non-chaperone function of secreted Hsp90alpha in tumour progression. Oncogene 36:2160-2171|