The purpose of this pilot proposal is to support the scientific development of a physician-scientist planning to work at the interface of basic cell biology, clinical dermatology and bone marrow transplantation. The scientific focus of this investigator is to understand the mechanisms that govern cellular proliferation, differentiation and death in mammalian skin. These mechanisms are regulated by the balance between cell growth and cell death due primarily to apoptosis. Ultraviolet radiation (UVR) in the A and B wavelengths (UVA or UVB) induces epidermal keratinocytes to either proliferate in response to sublethal doses of UVR or die in a programmed response. It is assumed that similar mechanisms regulate proliferation and apoptosis in cells of the hematopoietic system that are involved in proliferative skin diseases, cutaneous T-cell lymphomas (CTCL) and graft versus host disease (GVHD).
The Specific Aims of this proposal are to investigate how, when and why apoptosis is induced by UVR and other genotoxic agents. Numerous studies show that protein tyrosine kinases (PTKs) and phosphotyrosine phosphatases (PTPs) regulate cell proliferation by their effects on regulatory proteins in signal transduction pathways and the cytoskeleton proteins. The key elements to be studied in this grant are the timing and state of protein phosphorylation of regulatory proteins common to both cell proliferation and apoptotic pathways in keratinocytes and hematopoietics cells, primarily lymphocytes. The working hypothesis is that cells injured by a genotoxic agent proportionally activate or inactivate specific PTPs to regulate the state of phosphorylation of PTKs and other critical substrates. These responses are therefore proportionate to the severity and duration of the injury and depend upon when the injury occurs relative to the cell cycle. The interactions among these factors primarily then determines whether a temporary or sustained proliferative response is induced or an apoptotic pathway is irreversibly activated. If this hypothesis is true [based upon initial data] what specific mechanisms are involved in induction of apoptosis in specific cells, under defined conditions of injury, in synchronized cells and when in this process are specific PTPs activated? The addition of the MiCK apoptosis assay that allows monitoring apoptosis induction without having to irreversibly denature the cellular machinery of UVR injured cells permits novel experiments. The MiCK assay, in short, is a unique assay easily lending itself to investigating specific mechanisms regulating proliferation and apoptosis involved in lymphocyte mediated diseases and is complemented by the PTP renaturation assays developed by the PI. The initial focus of this pilot application is to define the prototypical responses to defined levels of and exposure to UVA and UVB radiation while developing and enriching the applicant's expertise in immunobiology.
| Russell, Shirley B; Smith, Joan C; Huang, Minjun et al. (2015) Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases. PLoS Genet 11:e1005568 |
| Velez Edwards, Digna R; Tsosie, Krystal S; Williams, Scott M et al. (2014) Admixture mapping identifies a locus at 15q21.2-22.3 associated with keloid formation in African Americans. Hum Genet 133:1513-23 |
| Duncan, F Jason; Silva, Kathleen A; Johnson, Charles J et al. (2013) Endogenous retinoids in the pathogenesis of alopecia areata. J Invest Dermatol 133:334-43 |
| Jandova, Jana; Shi, Mingjian; Norman, Kimberly G et al. (2012) Somatic alterations in mitochondrial DNA produce changes in cell growth and metabolism supporting a tumorigenic phenotype. Biochim Biophys Acta 1822:293-300 |
| Takahashi, Keiko; Mernaugh, Raymond L; Friedman, David B et al. (2012) Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc Natl Acad Sci U S A 109:1985-90 |
| Jandova, Jana; Eshaghian, Alex; Shi, Mingjian et al. (2012) Identification of an mtDNA mutation hot spot in UV-induced mouse skin tumors producing altered cellular biochemistry. J Invest Dermatol 132:421-8 |
| Sundberg, J P; Taylor, D; Lorch, G et al. (2011) Primary follicular dystrophy with scarring dermatitis in C57BL/6 mouse substrains resembles central centrifugal cicatricial alopecia in humans. Vet Pathol 48:513-24 |
| Harries, M J; Sun, J; Paus, R et al. (2010) Management of alopecia areata. BMJ 341:c3671 |
| Yang, Jinming; Splittgerber, Ryan; Yull, Fiona E et al. (2010) Conditional ablation of Ikkb inhibits melanoma tumor development in mice. J Clin Invest 120:2563-74 |
| Russell, Shirley B; Russell, James D; Trupin, Kathryn M et al. (2010) Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol 130:2489-96 |
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