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: 10033613
• 负责人: YANA G KAMBEROV
• 金额: $ 44.79万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033613
• 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; 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.

项目概要 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。尽管他们的 重要性，但人们对它们发育的细胞和分子机制知之甚少。这个提议 我们的工作表明转录因子 Engrailed-1 是小汗腺的独特决定因素和驱动因素 腺体形成定义诱导特定和分化的遗传和细胞机制 皮肤中的小汗腺。因此，该提案的目标是确定转录因子 在小汗腺发育过程中直接调节 Engrailed1 表达 (Aim1) 并定义 下游 Engrailed 1 依赖性转录程序，然后执行小汗腺形成 (Aim2)。 该提案整合了体内测试和细胞和分子成分的高通量发现 使用新生成的和现有的小鼠模型结合机制进行小汗腺发育 培养的人类皮肤细胞的解剖以及新型小鼠和人类单核之间的交叉验证 转录组数据集。因此，拟议的实验将描绘小汗腺发育 计划，为建立研究小汗腺的体外系统提供信息，并加强 更广泛地了解皮肤中外胚层附属物的命运和形成是如何建立的。从 从临床角度来看，我们的研究结果将为未来的小汗腺再生研究提供分子蓝图 体内的腺体，并且当这些器官受到损伤时，还为小汗腺的修复提供了新的干预点。 病理改变或损坏。