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

Engrailed-1 在小汗腺发育中的调节和功能的遗传和细胞机制

• 批准号: 10437853
• 负责人: YANA G KAMBEROV
• 金额: $ 43.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437853
• 关键词: Adopted; Alleles; Biology; Cell Nucleus; Cells; Cessation of life; ChIP-seq; Clinical; Collaborations; Complement; Data; Data Set; Development; Dissection; Eccrine Glands; Ectoderm; Enhancers; FBXO32 gene; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genomics; Gland; Goals; Hair; Hair follicle structure; Heat Exhaustion; Heat Losses; Human; Hyperthermia; In Vitro; Intervention; Knock-in Mouse; Knock-out; Knockout Mice; Limb structure; Medial; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutagenesis; Natural regeneration; Organ; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Physiologic Thermoregulation; Positioning Attribute; Regulation; Risk; Role; SP1 gene; Signal Transduction; Skin; System; Technology; Testing; Transcription Factor AP-1; Transcription Repressor; Transcriptional Activation; Validation; Work; appendage; base; cellular targeting; comparative; eccrine; evaporation; experimental study; gene repression; gland development; in vivo; in vivo evaluation; jun Oncogene; keratinocyte; knock-down; lentiviral-mediated; loss of function; mouse model; novel; overexpression; programs; repaired; transcription factor; transcriptome sequencing; transcriptomics; wound

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.

项目摘要 Eccerine腺体是人皮肤的主要附属物，是人类温度调节所必需的。尽管他们 重要的是，其发育的细胞和分子机制知之甚少。这个建议 建立在我们的工作基础上，这意味着转录因子属于1作为eccerine的独特决定因素和驱动力 腺体形成以定义诱导规范和分化的遗传和细胞机制 eccerine汗腺在皮肤中。因此，该提案的目标是确定转录因素 直接调节Eccrine腺体发育过程中的Engled1表达（AIM1）并定义 下游习惯了1依赖性转录程序，然后执行Eccrine Gland形成（AIM2）。 该建议将体内测试和高通量发现的细胞和分子成分发现 使用新生成和现有的鼠标模型与机械结合的Eccerine Gland开发 在培养的人皮细胞中解剖和新小鼠和人类单核之间的交叉验证 转录组数据集。因此，提出的实验将描绘出Eccerine的发育 计划，为建立一种研究e麦腺体的体外系统的努力，并增强 了解如何更广泛地在皮肤中建立外胚层附属物命运和形成。从 一个临床角度，我们的发现将为未来的研究提供分子蓝图 体内腺体，还提供新的干预点，以修复这些器官时 病理改变或损害。