Regulation of Sebaceous Gland Development

描述（由申请人提供）：本提案的长期目标是了解上皮干细胞对皮脂腺谱系的调控。皮脂腺与毛囊一起发育，表皮干细胞向特定谱系分化。当皮脂腺发育异常时，两种未解决的皮肤病理学，寻常痤疮和人类肿瘤，就会发展起来。然而，尽管这种细胞系在人类疾病中具有临床重要性，但人们对这种细胞系是如何形成的知之甚少。我的初步数据确定了一群单能祖细胞，它们通过转录抑制因子Blimpl的表达，调节进入皮脂腺的细胞输入，并引起上皮干细胞的过早活动。本研究的中心假设是，毛囊干细胞形成皮脂腺祖细胞对皮脂腺的正常形成和生物学至关重要。这一假设将在本次拨款申请中通过实验进行验证：1)通过Blimpl确定调节祖细胞命运的机制，2)确定调节干细胞谱系对皮脂腺命运的新型小分子，以及3)确定皮脂腺祖细胞在与干细胞室通信中的作用。许多细胞和分子机制将在指导阶段确定，并在本提案的独立阶段对特定基因和细胞机制进行后续研究。从拟议的实验中产生的数据将促进我们对皮脂腺发育和皮肤干细胞谱系的调节机制的理解。此外，这些拟议的研究将潜在地导致治疗皮脂腺疾病以及其他皮肤疾病和癌症的治疗方法的发展。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the regulation of epithelial stem cell commitment to the sebaceous gland lineage. The sebaceous gland develops along with the hair follicle as epidermal stem cells commit to a particular lineage and differentiate. When sebaceous development is aberrant, two unsolved dermatological pathologies, acne vulgaris and human tumors, develop. Yet, despite the clinical importance of this cell lineage in human disease, little is known about how this lineage forms. My preliminary data identifies a population of unipotent progenitor cells that by expression of the transcriptional repressor, Blimpl, regulates the cellular input into the sebaceous gland and elicits premature activity of epithelial stem cells. The central hypothesis tested by this proposal is that the formation of sebaceous progenitors from hair follicle stem cells is crucial for proper formation and biology of the sebaceous gland. This hypothesis will be tested in this grant application by experiments: 1) identifying mechanisms that regulate progenitor fate by Blimpl, 2) identifying novel small molecules that regulate stem cell lineage commitment to the sebaceous gland fate, and 3) determining the role of sebaceous progenitors in communication with the stem cell compartment. Many of the cellular and molecular mechanisms will be identified during the mentored phase, and follow up on particular genes identified and cellular mechanisms will be performed in the independent phase of this proposal. Data generated from the proposed experiments will advance our understanding of the mechanisms regulating sebaceous gland development and stem cell lineage commitment in the skin. In addition, these proposed studies will potentially lead to the development of therapeutic treatments for disorders of the sebaceous gland as well as other skin disorders and cancers.