|
Home>Faculty
List >Dr. Seykora
|
John T. Seykora, M.D., Ph.D. |
Education
| 1986 | B.A. | Biology with Honors | University of Chicago |
| 1986 | M.S. | Biochemistry | University of Chicago |
| 1992 | Ph.D. | Cell Biology | Rockefeller University |
| 1993 | M.D. | Cornell University Medical College |
Clinical Specialties
Dermatopathology, cutaneous diseases which exhibit abnormal keratinocyte differentiation;
e.g. neoplasia, psoriasis, and aging.
Research Summary
Our laboratory characterizes the molecular mechanisms that keratinocytes use to regulate growth and differentiation. In particular, we are interested in the mechanisms regulating tyrosine kinase signaling and the biological processes influenced by these signaling pathways. We employ a broad spectrum of experimental approaches in our work including: cell lines, primary cell culture, organotypic cultures, transgenic mouse models, and knock-out mouse models. Applying cellular and molecular biology techniques to these models, we characterize how tyrosine kinase signaling is regulated. We also utilize microarrays to characterize molecular features of normal and diseased human tissue. One primary goal of our work is to understand how keratinocytes transition from a stem cell compartment to a post-mitotic population of differentiating cells. What regulates this transitional step by keratinocytes is relevant to understanding the pathogenesis of many inflammatory skin disorders and cutaneous neoplasia.
The Src-family of tyrosine kinases plays an important biological role in epithelial cells; these kinases transmit signals from growth factor receptors to the nucleus that regulate growth and differentiation. Increased Src-kinase activity is associated with hyperplasias and neoplasia in most cell types. Our laboratory previously discovered a novel regulator of Src-kinases termed Srcasm (Src-activating and signaling molecule). Much of our work involves defining the mechanisms by which Srcasm regulates Src-kinase signaling in epithelial cells. This work will yield novel insights into Src kinase signaling and the regulation of epithelial cell growth.
Some observations made by our laboratory over the past few years:
1. Srcasm levels are decreased in human cutaneous SCC and associated precursor lesions compared with normal skin.
2. Src-kinase activity is markedly elevated in these lesions compared with normal skin.
3. Increasing Fyn levels in cells in vivo can produce hyperplasia and cutaneous SCC formation in vivo.
4. Raising Srcasm levels can inhibit hyperplasia and tumor formation associated with elevated SFK levels.
5. The mechanism by which Srcasm downregulates Src-kinase requires intact endosomal/lysosomal function.
Projects
1) Characterization of the K14-Fyn transgenic mouse as a model for psoriasis-our K14-Fyn mouse exhibits epidermal hyperplasia, mixed dermal and cutaneous inflammation, and activation of STAT3. All of these features are typical of human psoriasis. Additional characterization of this transgenic mouse as a potential model of psoriasis is planned.
2) Srcasm downregulates activated Src-kinases in cells through a mechanism that requires the endosomal-lysosomal pathway. Data suggests that Srcasm associates with known components of the endocytic pathway. This project would involve characterizing the effect of mutant forms of Srcasm that do not associate with endosomal/lysosomal molecules on downregulation of activated Src kinases.
3) Effects of Srcasm on cutaneous carcinogenesis. We have a transgenic model of cutaneous carcinogenesis that develops squamous cell carcinomas. Native Srcasm can inhibit formation of these tumors. More work to characterize how mutant forms of Srcasm influence tumor formation is planned.
4) Wound healing-activation of Src kinases in necessary for keratinocyte growth and motility. Increased Src kinase activity and decreased Srcasm levels are present at the leading edge of healing human wounds. We are using in vivo and in vitro models to better characterize these observations
5) How loss of Srcasm effects epithelial biology. Using siRNA and knock-out mice we are characterizing how loss of Srcasm function alters cell signaling and growth.
Dr. Seykora's Lab Personnel:
Weijie Li, Research Specialist
Christine Marshall, Research Specialist
Elias Ayli, Post Doctoral Fellow
Tamer Salah, Visiting Scholar
Ryan Fortna, Resident
Thomas Griffin, Post Bacculaureate Student
Selected Publications
277:2812-2822. 2002. 2004, 280: 6036-46. 2005. 282: 1161-69. 2007. 34: 160-65. 2007. published on-line October 9 2007|
Privacy Statement | Legal
Disclaimer
The University of Pennsylvania Health System. © 2005. The Trustees of University of Pennsylvania |