Bone Morphogentic Protein signaling in the control of skin development, hair grow

描述(申请人提供)：在过去的十年中，研究表明，关键的信号通路(Wnt、Hedgehog、Notch、TGF2/BMP等)调节皮肤发育的物质在皮肤癌的发生中也起着重要作用。骨形态发生蛋白(BMP)信号是皮肤发育和肿瘤抑制的强大调节因子，我们的长期目标是更深入地了解它在角质形成细胞中控制正常细胞和肿瘤细胞命运的作用，目标是开发皮肤再生和肿瘤的新疗法。在过去五年的资助中，我们的研究集中在描绘BMP拮抗剂Noggin和BMP-Smad信号通路在控制正常皮肤发育和毛发生长中的作用。我们在下一个资金阶段的研究计划将把这些发现与过去几年取得的主要优势结合起来，这些优势揭示了控制皮肤发育和肿瘤发生的机制以及BMP信号在调节皮肤干细胞的维持和活性方面正在出现的作用。具体地说，我们将进一步探讨BMP信号在皮肤中的肿瘤抑制功能的潜在机制，并将测试BMP信号调节皮肤上皮干细胞和/或其后代的活性并通过拮抗关键的致癌信号通路(Wnt和Shh)来阻止其肿瘤转化的假设。这一假说将通过三个特定的目标来解决：1.确定BMP-Smad信号在正常毛囊干细胞和/或其后代向肿瘤前体细胞表型重编程中的作用。2.明确BMP-Smad通路在正常毛囊干细胞/其后代和肿瘤前体细胞中调节Wnt信号的机制。3.明确BMP-Smad信号在调节毛囊干细胞及其后代Hedgehog通路活性和皮肤肿瘤发生中的作用和靶点。这一提议的成功实现将为我们对皮肤中正常和肿瘤干细胞活性调节机制的认识提供新的重要见解，并可能为通过调节干细胞活性来治疗组织再生和肿瘤过程提供一种新的策略。 与公共健康相关：皮肤有一群未分化的细胞，也被称为干细胞，它们参与表皮和毛囊的再生，也在皮肤肿瘤的发展中发挥作用。目前研究的目标是了解属于骨形态发生蛋白家族的生物活性分子如何调节皮肤再生和肿瘤发生的过程。这项工作将为干细胞生物学提供新的见解，并将有助于建立新的治疗方法，在皮肤再生和致癌过程中调节干细胞的活性。

DESCRIPTION (provided by applicant): During the last decade, it was shown that key signaling pathways (Wnt, Hedgehog, Notch, TGF2/BMP, etc.) that regulate skin development also play important roles in the development of skin cancers. Bone morphogenetic protein (BMP) signaling is a powerful regulator of skin development and tumor suppressor, and our long-term objectives are to pursue a deeper understanding of its role in the control of normal versus neoplastic cell fate decision in the keratinocytes with goals to develop new therapies for skin regeneration and neoplasias. During previous five years of funding, our studies were focused on delineating the roles for BMP antagonist Noggin and BMP-Smad signaling pathway in the control of normal skin development and hair growth. Our research program for next funding period will integrate these findings with major advantages achieved during last few years that revealed remarkable similarities in the mechanisms controlling skin development and tumorigenesis, as well as with the emerging role for BMP signaling in regulating the maintenance and activity of cutaneous stem cells. Specifically, we will further pursue the mechanisms underlying tumor suppressor function of the BMP signaling in the skin and will test the hypothesis that BMP signaling regulates the activity of epithelial stem cells and/or their progenies in the skin and prevents their neoplastic transformation by antagonizing key pro-oncogenic signaling pathways (Wnt and Shh). This hypothesis will be addressed via three specific aims: 1. Define the role of the BMP-Smad signaling in the reprogramming of normal hair follicle stem cells and/or their progenies towards the tumor progenitor cell phenotype. 2. Define the mechanisms underlying involvement of the BMP-Smad pathway in modulating the Wnt signaling in normal hair follicle stem cells/their progenies and in neoplastic progenitor cells. 3. To define the role and targets for BMP-Smad signaling in regulating the activity of Hedgehog pathway in hair follicle stem cells/their progenies and skin tumorigenesis. Successful realization of this proposal will provide new important insights into our knowledge on the mechanisms regulating the activity of normal and neoplastic stem cells in the skin and may provide a novel strategy for therapeutic management of tissue regeneration and neoplastic processes via modulation of stem cell activity. PUBLIC HEALTH RELEVANCE: Skin has a population of undifferentiated cells also called as stem cells that are involved in regeneration of the epidermis and hair follicles and also play a role in the development of skin tumors. The goal of current study is to understand how biologically active molecules that belong to the family of bone morphogenetic proteins regulate a process of skin regeneration and tumorigenesis. This work will provide new insights into stem cell biology and will help in establishing new therapeutic approaches for modulating the activity of stem cells during skin regeneration and carcinogenesis.