Regulation of Sebaceous Gland Development

这项建议的长期目标是了解上皮干细胞对皮脂腺谱系的调节作用。皮脂腺与毛囊一起发育，因为表皮干细胞致力于特定的谱系和分化。当皮脂腺发育异常时，两种尚未解决的皮肤病--寻常痤疮和人类肿瘤--就会出现。然而，尽管这种细胞谱系在人类疾病中具有临床重要性，但人们对这种谱系是如何形成的知之甚少。我的初步数据表明，通过转录抑制因子Blimpl的表达，可以调节细胞对皮脂腺的输入，并引发上皮干细胞的过早活动，从而确定了一组功能单一的祖细胞。这一建议检验的中心假设是，毛囊干细胞形成皮脂祖细胞对于皮脂腺的正常形成和生物学至关重要。这一假说将通过实验来验证：1)确定Blimpl调节祖细胞命运的机制；2)确定皮脂祖细胞在毛囊干细胞室的通讯中的作用。在这一奖项的指导阶段，我已经确定了一些调节皮脂腺发育的潜在机制，并将对已确定的特定基因进行后续研究，并将在该计划的独立阶段执行细胞机制。拟议中的实验产生的数据将促进我们对皮脂腺发育和皮肤中干细胞谱系承诺的调控机制的理解。此外，这些拟议的研究可能会导致皮脂腺疾病以及其他皮肤病和癌症的治疗方法的开发。

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.