Genetic and Cellular Mechanisms of Engrailed-1 Regulation and Function in Eccrine Sweat Gland Development

项目总结 小汗腺是人体皮肤的主要附属物，是人体体温调节所必需的。尽管他们 由于其重要性，其发育的细胞和分子机制知之甚少。这项建议 建立在我们工作的基础上，转录因子Engraated-1是内分泌的唯一决定因素和驱动因素 腺体形成，以确定诱导指定和分化的遗传和细胞机制 皮肤上的汗腺分泌。因此，这项建议的目标是确定转录因子 在内分泌腺发育过程中直接调节Engrailed1的表达(Aim1)，并定义 下游递增的1依赖转录程序，然后执行小汗腺形成(AIM2)。 该方案集成了体内测试和高通量发现的细胞和分子成分 利用新产生的和现有的小鼠模型结合机械学来开发小汗腺 培养的人皮肤细胞的解剖及新型小鼠与人单核细胞的交叉验证 转录数据集。因此，拟议的实验将描绘出内分泌腺的发育。 计划，通知努力建立一个体外系统，在其中研究分泌腺，并加强 更广泛地理解外胚层附属物的命运和形成是如何在皮肤中建立的。从… 从临床角度来看，我们的发现将为未来再生外分泌的研究提供分子蓝图。 体内的腺体，也为修复内分泌腺提供了新的干预点，当这些器官被 病理性的改变或损坏。

PROJECT SUMMARY Eccrine glands are the major appendage of human skin and required for human thermoregulation. Despite their importance, the cellular and molecular mechanisms of their development are poorly understood. This proposal builds on our work implicating the transcription factor Engrailed-1 as a unique determinant and driver of eccrine gland formation to define genetic and cellular mechanisms that induce the specification and differentiation of eccrine sweat glands in the skin. Accordingly, the goals of this proposal are to identify the transcription factors that directly modulate Engrailed1 expression during eccrine gland development (Aim1) and to define the downstream Engrailed 1-dependent transcriptional program that then executes eccrine gland formation (Aim2). This proposal integrates in vivo testing and high-throughput discovery of cellular and molecular components of eccrine gland development using both newly generated and existing mouse models combined with mechanistic dissection in cultured human skin cells and cross-validation between novel mouse and human single nucleus transcriptomic datasets. As such, the proposed experiments will delineate the eccrine gland developmental program, inform efforts to establish an in vitro system in which to study eccrine glands, and enhance understanding of how ectodermal appendage fate and formation are established in the skin more broadly. From a clinical perspective, our findings will provide a molecular blueprint for future studies to regenerate eccrine glands in vivo and also offer novel points of intervention for repair of eccrine glands when these organs are pathologically altered or damaged.