Identification of tumor progenitor cells (cancer stem cells) in both hematological and solid malignancies suggests that tumor progenitor cells 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 tumorigenesis. 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 understand 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 cell 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 signaling 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 will 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 stem 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 ability to promote treatment of acute and chronic wounds

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AR056771-01A1
Application #
7741010
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Baker, Carl
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$124,227
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
Sharova, Tatyana Y; Poterlowicz, Krzysztof; Botchkareva, Natalia V et al. (2014) Complex changes in the apoptotic and cell differentiation programs during initiation of the hair follicle response to chemotherapy. J Invest Dermatol 134:2873-2882
Mardaryev, Andrei N; Gdula, Michal R; Yarker, Joanne L et al. (2014) p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells. Development 141:101-11
Gdula, Michal R; Poterlowicz, Krzysztof; Mardaryev, Andrei N et al. (2013) Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis. J Invest Dermatol 133:2191-201
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
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
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
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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