Keloids represent an insidious disease process that afflicts primarily young, minority patients leaving them with disfigurement, and occasionally, disability. This research application seeks to address the observation that keloid-derived skin cells appear to have an aberrant genotypic response compared to normal-derived skin cells to stress in the form of serum stimulation and physical strain. This phenomenon will be examined by focusing on the differential transcriptional response of the TGF-beta2 gene to serum stimulation in keratinocytes. The three specific aims of this application are to determine the promoter elements responsible for this differential response, identify the signal transduction pathways mediating the response, and identify additional genes that may be coordinately regulated with TGF-beta2 and contributing to the keloid Iphenotype. In addition to answering important questions about keloid biology, this application will also serve !to provide the nit a support for the academic career of the Principal Investigator. He has demonstrated a long record of commitment to biomedical research and has chosen wound healing and surgery as the field he wishes to pursue. His initial goal is to establish a laboratory in wound healing that is fully supported through extramural funding. The long term goal of the Principal Investigator is to use the knowledge derived from his studies in wound healing to better understand the biology of skin. This information can then translated into clinical applications through the treatment of chronic wounds or excessive scarring, and can also be used in tissue engineering to synthesize artificial skin that can be applied to clinical problems in reconstruction, including burns. A career development program is detailed that is designed to educate the Principal Investigator in the proper, ethical conduct of research. Plans have been developed to improve specific skills to promote his career development. These include experimental design, grantsmanship, interactions with the surgical and scientific community, and manuscript preparation and review. This project will be carried out under the tutelage of a highly successful Mentor at Stanford University Medical School. This is one of the leading biomedical research institutions in the nation, and it has implemented multiple programs aimed at improving translational medicine. The institution has every resource needed to carry out this project in addition to a number of experts in the field to provide advice.
| Butler, Paris D; Wang, Zhen; Ly, Daphne P et al. (2011) Unfolded protein response regulation in keloid cells. J Surg Res 167:151-7 |
| Haurani, Mounir J; Foreman, Kenneth; Yang, James J et al. (2009) 5-Fluorouracil treatment of problematic scars. Plast Reconstr Surg 123:139-48; discussion 149-51 |
| Butler, Paris D; Ly, Daphne P; Longaker, Michael T et al. (2008) Use of organotypic coculture to study keloid biology. Am J Surg 195:144-8 |
| Xia, Wei; Kong, Wuyi; Wang, Zhen et al. (2007) Increased CCN2 transcription in keloid fibroblasts requires cooperativity between AP-1 and SMAD binding sites. Ann Surg 246:886-95 |
| Malladi, Preeti; Xu, Yue; Yang, George P et al. (2006) Functions of vitamin D, retinoic acid, and dexamethasone in mouse adipose-derived mesenchymal cells. Tissue Eng 12:2031-40 |
| Xia, Wei; Phan, Toan-Thang; Lim, Ivor J et al. (2006) Differential transcriptional responses of keloid and normal keratinocytes to serum stimulation. J Surg Res 135:156-63 |
| Wang, Zhen; Fong, Kenton D; Phan, Toan-Thang et al. (2006) Increased transcriptional response to mechanical strain in keloid fibroblasts due to increased focal adhesion complex formation. J Cell Physiol 206:510-7 |
