Regulation of Sebaceous Gland Development

描述(由申请人提供)：这项建议的长期目标是了解皮脂腺谱系上皮干细胞承诺的调节。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。我的初步数据确定了一组功能强大的前体细胞，它们通过转录抑制因子Blimpl的表达，调节细胞输入皮脂腺，并引发上皮干细胞的过早活动。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。这一假说将在这项赠款申请中通过实验得到验证：1)确定通过Blimpl调节祖细胞命运的机制，2)确定调节皮脂腺命运的干细胞谱系的新小分子，以及3)确定皮脂腺前体在与干细胞室沟通中的作用。许多细胞和分子机制将在指导阶段确定，后续确定的特定基因和细胞机制将在该提案的独立阶段执行。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。

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.