Regulation of Sebaceous Gland Development

这项建议的长期目标是了解上皮干细胞向皮脂腺谱系的定向调节。皮脂腺沿着毛囊发育，因为表皮干细胞致力于特定的谱系并分化。当皮脂腺发育异常时，两种未解决的皮肤病学病理，寻常痤疮和人类肿瘤，发展。然而，尽管这种细胞谱系在人类疾病中具有临床重要性，但对这种谱系如何形成知之甚少。我的初步数据鉴定了一群单能祖细胞，其通过表达转录阻遏物Blimpl来调节进入皮脂腺的细胞输入并消除上皮干细胞的过早活性。该提议所验证的中心假设是，从毛囊干细胞形成皮脂腺祖细胞对于皮脂腺的正确形成和生物学至关重要。该假设将在本授权申请中通过实验进行测试：1）鉴定Blimpl调节祖细胞命运的机制，以及2）确定皮脂腺祖细胞在与毛囊干细胞室通信中的作用。在该奖项的指导阶段，我已经确定了一些调节皮脂腺发育的潜在机制，并将跟踪确定的特定基因，细胞机制将在本提案的独立阶段进行。从拟议的实验中产生的数据将促进我们对调节皮脂腺发育和皮肤中干细胞谱系定型的机制的理解。此外，这些拟议的研究将可能导致开发用于皮脂腺疾病以及其他皮肤疾病和癌症的治疗方法。

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 prelimary 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, and 2) determining the role of sebaceous progenitors in communication with the hair follicle stem cell compartment. During the mentored phase of this award, I have identified a number of potential mechanisms that regulate sebaceous gland developoment and will 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 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.