This continuation research proposal (in its 12th year) is a total departure from its original title (on ?Mechanism of Human Dermal Fibroblast Motility?), since our discovery of the keratinocyte-secreted form of heat shock protein-90alpha (Hsp90?) as a potent pro-motility factor and a novel wound healing agent by our laboratory in 2007 (Li et al, EMBO J). The development of human recombinant Hsp90? protein as a new treatment for (chronic) diabetic foot ulcers entered its industrial (GMP) phase in 2013 and is under preparations for clinical trials. During the previous funding cycle of Hsp90?, we established a new pig wound healing model for burns that recapitulates the clinical characteristics of burn wounds in humans. Using this model, we have made and reported a new discovery for topically applied Hsp90? to become potentially the first therapeutic treatment of burn wounds (Bhatia et al, Molecular Therapy, 2016). Here is the reason why. Burn injuries are different from all other (acute or chronic) types of wounds by going through an unique event of so-called secondary burn wound progression following the injury, in which a burn expands both horizontally and vertically from its initial boundary to a larger area within the first 1-2 weeks. Therefore, any effective therapeutics must show dual abilities of 1) preventing the secondary burn wound progression and 2) thereafter promoting burn wound re-epithelialization (i.e. closure). Currently there is no FDA-approved therapeutics for burns. We reported that topically applied Hsp90? protein is such a dual functional therapeutics that promotes burn wound healing. First, Hsp90? prevents the secondary burn wound progression by protecting the surrounding cells from undergoing heat-induced Caspase-3 activation and apoptosis. Thereafter, Hsp90? accelerates burn wound healing by stimulating keratinocyte migration-led re-epithelialization, leading to wound closure. This is the first report for a single polypeptide that shows such dual therapeutic functions as required for effective treatment of burn wounds. The goal of this continuation proposal is to elucidate 1) how the secondary burn wound progression takes place, i.e. necrosis versus apoptosis, and 2) how topical Hsp90? prevents secondary burn wound progression. Finally, we will establish a new therapeutic entity (NTE), called Fragment-8, of Hsp90? for drug development. Accomplishment of these preclinical studies will lay the foundation for clinical trials. 1

Public Health Relevance

The discovery of the keratinocyte-secreted form of the intracellular chaperone protein called heat shock protein alpha (Hsp90?) as a potent wound healing promoting factor in 2007 continues to show new promises, after the development of its full-length and its F-5 fragment entered the industrial phase in 2013. During the previous 4-year funding cycle, we discovered the second important property of topically applied Hsp90?: preventing heat-caused cell death and the secondary burn wound progression, a distinct clinical event for burns. Together with its already known property of promoting the keratinocyte migration-driven wound re-epithelialization, outcomes of this research proposal may lead to a new and the first topical treatment (in forms of cream and/or spray) of burn wounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Somers, Scott D
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Guo, Jiacong; Jayaprakash, Priyamvada; Dan, Jian et al. (2017) PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion. Mol Cell Biol 37:
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
Dong, Hangming; Zou, Mengchen; Bhatia, Ayesha et al. (2016) Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90?) to Survive a Hostile Hypoxic Environment. Sci Rep 6:20605
Bhatia, Ayesha; O'Brien, Kathryn; Chen, Mei et al. (2016) Keratinocyte-Secreted Heat Shock Protein-90alpha: Leading Wound Reepithelialization and Closure. Adv Wound Care (New Rochelle) 5:176-184
Bhatia, Ayesha; O'Brien, Kathryn; Chen, Mei et al. (2016) Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs. Mol Ther Methods Clin Dev 3:16041
Woodley, David T; Wysong, Ashley; DeClerck, Brittany et al. (2015) Keratinocyte Migration and a Hypothetical New Role for Extracellular Heat Shock Protein 90 Alpha in Orchestrating Skin Wound Healing. Adv Wound Care (New Rochelle) 4:203-212
Jayaprakash, Priyamvada; Dong, Hangming; Zou, Mengchen et al. (2015) Hsp90? and Hsp90? together operate a hypoxia and nutrient paucity stress-response mechanism during wound healing. J Cell Sci 128:1475-80
O'Brien, Kathryn; Bhatia, Ayesha; Tsen, Fred et al. (2014) Identification of the critical therapeutic entity in secreted Hsp90? that promotes wound healing in newly re-standardized healthy and diabetic pig models. PLoS One 9:e113956
Li, Wei; Tsen, Fred; Sahu, Divya et al. (2013) Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: intentionally or unintentionally. Int Rev Cell Mol Biol 303:203-35
Tsen, Fred; Bhatia, Ayesha; O'Brien, Kathryn et al. (2013) Extracellular heat shock protein 90 signals through subdomain II and the NPVY motif of LRP-1 receptor to Akt1 and Akt2: a circuit essential for promoting skin cell migration in vitro and wound healing in vivo. Mol Cell Biol 33:4947-59

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