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，研究表明，调节皮肤发育的关键信号通路（Wnt、Hedgehog、Notch、TGF2/BMP等）在皮肤癌的发生中也起着重要作用。骨形态发生蛋白（Bone morphogenetic protein， 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其在角质形成细胞中正常细胞与肿瘤细胞命运决定的控制中的作用，以开发新的皮肤再生和肿瘤治疗方法。在过去五年的资助中，我们的研究主要集中在描述BMP拮抗剂Noggin和BMP- smad信号通路在控制正常皮肤发育和头发生长中的作用。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机制的显着相似性，以及BMP信号在调节皮肤干细胞维持和活性方面的新作用。具体来说，我们将进一步研究皮肤中BMP信号的抑瘤功能机制，并验证BMP信号调节皮肤上皮干细胞和/或其后代细胞的活性，并通过拮抗关键的促癌信号通路（Wnt和Shh）来阻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。确定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. 确定BMP-Smad通路在正常毛囊干细胞/其子代细胞和肿瘤祖细胞中调节Wnt信号的潜在机制。3. 明确BMP-Smad信号在毛囊干细胞/其子代和皮肤肿瘤发生过程中调控Hedgehog通路活性的作用和靶点。这一建议的成功实现将为我们对调节皮肤正常和肿瘤干细胞活性的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新的策略。

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.