Identification of tumor progenitor cells (cancer stem cells) in both hematological and soUd malignancies suggests that tumor progenitor ceUs may be a common phenomenon for most neoplastic processes. However, despite a considerable progress in identification of molecular mechanisms underlying the development of cutaneous neoplasias, very little is known about involvement of stem cells and signaling pathways regulating their activity in the skin tumorogenesis.The long-term scientific career goals are to develop into an independent investigator in academic experimental dermatology and achieve a progress in understanding of molecular mechanisms of epithelial stem cell quiescence;investigate molecular bases of epithelial-mesenchymal interactions during stem cell neoplastic transformation and the development of therapy for patients with skin disorders. The career development will be focused exclusively on those areas and modem methods of dermatological research, in which I have not been trained before.The goal of this proposal is to characterize molecular signature of normal and neoplastic epithelial stem cells in skin and to xmderstand molecular mechanisms underlying the role of BMP signaling in reprogramming of normal stem cells towards tumor progenitor cell phenotype. We hypothesize that BMP signaling inhibits the activity of normal epithelial stem cells and prevents their reprogramming towards neoplastic phenotype. To address this hypothesis and pursue mechanisms underlying the involvement of BMP signaling in regulation of stem ceU activity, we propose two specific aims: l)Compare molecular signature and BMP target genes in stem cells isolated from normal mouse skin and from hair follicle-derived tumors of K14-Noggin transgenic mice. Double Keratin 15-EGFP/Keratin 14-Noggin transgenic mice will be generated and used as basic model for this study. 2).Define whether inhibition of BMP signahng in normal skin stem cells would result in their reprogramming towards the tumor stem cell phenotype. Normal epithelial stem cells from K15-EGFP mouse skin wiU be isolated and after lentiviral-based ablation of BMPR-IA, their ability to form tumors in vivo will be tested in skin reconstitution assay.

Public Health Relevance

Skin has a population of undifferentiated cells also called as stenn cells that involved in skin regeneration. The goal of our study is to understand how family of molecules called Bone Morphogenetic Proteins regulates a process of stem cell renewal. This work should provide insights into the stem cell biology and related processes of carcinogenesis, and may lead to new approaches of cancer prevention and treatment and may improve our abilitv to promote treatment of acute and chronic wounds

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Baker, Carl
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Boston University
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Ahmed, Mohammed I; Alam, Majid; Emelianov, Vladimir U et al. (2014) MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway. J Cell Biol 207:549-67
Lewis, Christopher J; Mardaryev, Andrei N; Poterlowicz, Krzysztof et al. (2014) Bone morphogenetic protein signaling suppresses wound-induced skin repair by inhibiting keratinocyte proliferation and migration. J Invest Dermatol 134:827-837
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Botchkarev, Vladimir A; Gdula, Michal R; Mardaryev, Andrei N et al. (2012) Epigenetic regulation of gene expression in keratinocytes. J Invest Dermatol 132:2505-21
Mardaryev, Andrei N; Meier, Natalia; Poterlowicz, Krzysztof et al. (2011) Lhx2 differentially regulates Sox9, Tcf4 and Lgr5 in hair follicle stem cells to promote epidermal regeneration after injury. Development 138:4843-52
Ahmed, Mohammed I; Mardaryev, Andrei N; Lewis, Christopher J et al. (2011) MicroRNA-21 is an important downstream component of BMP signalling in epidermal keratinocytes. J Cell Sci 124:3399-404
Fessing, Michael Y; Mardaryev, Andrei N; Gdula, Michal R et al. (2011) p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis. J Cell Biol 194:825-39
Sharov, Andrey A; Schroeder, Mandy; Sharova, Tatyana Y et al. (2011) Matrix metalloproteinase-9 is involved in the regulation of hair canal formation. J Invest Dermatol 131:257-60

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