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Articles by David T. Woodley
Total Records ( 2 ) for David T. Woodley
  Chieh-Fang Cheng , Jianhua Fan , Mark Fedesco , Shengxi Guan , Yong Li , Balaji Bandyopadhyay , Alexandra M. Bright , Dalia Yerushalmi , Mengmeng Liang , Mei Chen , Yuan-Ping Han , David T. Woodley and Wei Li
  Jump-starting and subsequently maintaining epidermal and dermal cell migration are essential processes for skin wound healing. These events are often disrupted in nonhealing wounds, causing patient morbidity and even fatality. Currently available treatments are unsatisfactory. To identify novel wound-healing targets, we investigated secreted molecules from transforming growth factor α (TGFα)-stimulated human keratinoytes, which contained strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein 90α (hsp90α) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGFα causes rapid membrane translocation and subsequent secretion of hsp90α via the unconventional exosome pathway in the cells. Secreted hsp90α promotes both epidermal and dermal cell migration through the surface receptor LRP-1 (LDL receptor-related protein 1)/CD91. The promotility activity resides in the middle domain plus the charged sequence of hsp90α but is independent of the ATPase activity. Neutralizing the extracellular function of hsp90α blocks TGFα-induced keratinicyte migration. Most intriguingly, unlike the effects of canonical growth factors, the hsp90α signaling overrides the inhibition of TGFβ, an abundant inhibitor of dermal cell migration in skin wounds. This finding provides a long-sought answer to the question of how dermal cells migrate into the wound environment to build new connective tissues and blood vessels. Thus, secreted hsp90α is potentially a new agent for wound healing.
  David T. Woodley , Yingping Hou , Sabrina Martin , Wei Li and Mei Chen
  Type VII collagen (C7) is a major component of anchoring fibrils, structures that mediate epidermal-dermal adherence. Mutations in gene COL7A1 encoding for C7 cause dystrophic epidermolysis bullosa (DEB), a genetic mechano-bullous disease. The biological consequences of specific COL7A1 mutations and the molecular mechanisms leading to DEB clinical phenotypes are unknown. In an attempt to establish genotype-phenotype relationships, we generated four individual substitution mutations that have been associated with recessive DEB, G2049E, R2063W, G2569R, and G2575R, and purified the recombinant mutant proteins. All mutant proteins were synthesized and secreted as a 290-kDa mutant C7 α chain at levels similar to wild type C7. The G2569R and G2575R glycine substitution mutations resulted in mutant C7 with increased sensitivity to protease degradation and decreased ability to form trimers. Limited proteolytic digestion of mutant G2049E and R2063W proteins yielded aberrant fragments and a triple helix with reduced stability. These two mutations next to the 39-amino acid helical interruption hinge region caused local destabilization of the triple-helix that exposed an additional highly sensitive proteolytic site within the region of the mutation. Our functional studies demonstrated that C7 is a potent pro-motility matrix for skin human keratinocyte migration and that this activity resides within the triple helical domain. Furthermore, G2049E and R2063W mutations reduced the ability of C7 to support fibroblast adhesion and keratinocyte migration. We conclude that known recessive DEB C7 mutations perturb critical functions of the C7 molecule and likely contribute to the clinical phenotypes of DEB patients.
 
 
 
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