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

描述（由申请人提供）：在过去的十年中，显示了关键信号传导途径（Wnt、Hedgehog、Notch、TGF 2/BMP等）调节皮肤发育的基因也在皮肤癌的发展中起重要作用。骨形态发生蛋白（BMP）信号传导是皮肤发育和肿瘤抑制的强大调节剂，我们的长期目标是更深入地了解其在控制角质形成细胞中正常细胞与肿瘤细胞命运决定中的作用，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，我们的研究重点是描述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。我们下一个资助期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的显着相似性，以及BMP信号在调节皮肤干细胞的维持和活性中的新兴作用。具体而言，我们将进一步追求皮肤中BMP信号传导的肿瘤抑制功能的潜在机制，并将测试BMP信号传导调节皮肤中上皮干细胞和/或其后代的活性并通过拮抗关键的促癌信号传导途径（Wnt和Shh）来防止其肿瘤转化的假设。这一假设将通过三个具体目标来解决：1。定义BMP-Smad信号在正常毛囊干细胞和/或其后代向肿瘤祖细胞表型重编程中的作用。2.定义BMP-Smad通路参与调节正常毛囊干细胞/其后代和肿瘤祖细胞中Wnt信号传导的潜在机制。3.目的明确BMP-Smad信号通路在毛囊干细胞及其后代Hedgehog通路活性调节和皮肤肿瘤发生中的作用及靶点。成功实现这一建议将提供新的重要见解，我们的知识的机制，调节正常和肿瘤干细胞在皮肤中的活性，并可能提供一种新的策略，通过调节干细胞活性的组织再生和肿瘤过程的治疗管理。

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.