Molecular mechanism of neuronal control in sweat gland development

神经元控制汗腺发育的分子机制

• 批准号: 10928886
• 负责人: Catherine Pei-Ju Lu
• 金额: $ 37.21万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10928886
• 关键词: 3-Dimensional; Ablation; Acetylcholine; Affect; Binding; Body Temperature; Brain Injuries; Burn injury; Calcium; Cell Culture System; Cell Differentiation process; Cell Maintenance; Cells; Cessation of life; Chemicals; Data; Defect; Denervation; Development; Duct (organ) structure; Ductal Epithelial Cell; Eccrine Glands; Equilibrium; Fluorescence-Activated Cell Sorting; Gene Expression; Gland; Glandular Cell; Heat Stroke; Heterogeneity; Homeostasis; Human; Hyperthermia; Image; Imaging technology; Knockout Mice; Light; Long-Term Effects; Mediating; Modeling; Molecular; Morphogenesis; Morphology; Multipotent Stem Cells; Mus; Muscarinic Acetylcholine Receptor M3; Myoepithelial cell; Natural regeneration; Nerve; Nervous System; Neurons; Neurotoxins; Neurotransmitters; Norepinephrine; Organ failure; Oxidopamine; Pathway interactions; Patients; Persons; Physiologic Thermoregulation; Proliferating; Role; Signal Transduction; Skin; Skin Tissue; Specific qualifier value; Sweat Glands; Sweating; Testing; Tissue Engineering; Tissues; Water; beta-2 Adrenergic Receptors; cell fate specification; conditional knockout; epidermal stem cell; gland development; insight; mouse genetics; mouse model; nerve supply; neurotransmission; neurotransmitter release; novel; progenitor; protein expression; receptor binding; regenerative therapy; response; sarcolipin; severe burns; single-cell RNA sequencing; skin regeneration; stem cell fate; stem cell fate specification; stem cells; therapeutic development

PROJECT SUMMARY Eccrine sweat glands are the most abundant glands in human skin and are essential for thermoregulation and water balance. Patients with severe burn injuries and congenital sweat gland deficiencies cannot properly maintain body temperature, which can lead to heat stroke and organ failure. The recent identification of multipotent stem cells in sweat glands presents great potential to help these people to thermoregulate efficiently by opening the way for de novo sweat gland regeneration. Nonetheless, regeneration of fully functional sweat glands will require better understanding of the endogenous signals that normally regulate differentiation of sweat gland stem cells. Precise innervation and neuronal control are indispensable for sweat glad function since neuronal signals elicit sweating, and further, as we previously discovered in our lab, these signals are critical for sweat gland maturation. Sweat glands and neurons rely on each other for precise co-development. However, very little is known about how neuronal inputs influence sweat gland development, especially sweat gland stem cells. We hypothesize that neuronal signals are critical for the specification of sweat gland stem cells during development. Using mouse sweat glands as a model, we will investigate the molecular changes in sweat gland stem cells during development when lacking innervation, and further identify the downstream pathway within sweat gland stem cells that mediate the effect of neurotransmitters upon stem cell maintenance. Through combined use of mouse genetics, immunofluorescent confocal and light sheet imaging, single-cell RNA sequencing, fluorescence-activated cell sorting, and tissue explant and cell culture systems, we plan to: 1) investigate the effect of denervation during sweat gland development and homeostasis; 2) dissect the roles of specific neurotransmitters in sweat ducts and sweat gland development; and 3) understand the mechanism(s) by which calcium mediates neuronal control of sweat gland stem cell fate. Completion of our proposed studies will provide novel insights into molecular mechanisms by which nervous system influence sweat gland morphogenesis and cell fate determination at different developmental stages. Further, our results will provide groundbreaking insight into how sweat glands and nerves co-develop into a functional unit, which will in turn facilitate regenerative therapies for patients suffering from sweating deficiency.

项目摘要 Eccerine汗腺是人皮肤中最丰富的腺体，对于温度调节和 水平衡。严重烧伤受伤和先天汗腺缺陷的患者无法正确 保持体温，这可能导致中风和器官衰竭。最近的识别 汗腺中的多能干细胞具有帮助这些人有效调节的巨大潜力 通过为从头汗腺再生开辟道路。尽管如此，功能性汗水的再生 腺体将需要更好地理解通常调节汗液分化的内源信号 腺干细胞。精确的神经支配和神经元控制对于汗水感到不可或缺，因为 神经元信号引起了出汗，而且正如我们之前在实验室中发现的那样，这些信号对于 汗腺成熟。汗腺和神经元相互依赖于精确的共同开发。然而， 关于神经元输入如何影响汗腺发育，尤其是汗腺茎，知之甚少 细胞。我们假设神经元信号对于汗腺干细胞的规范至关重要 在开发过程中。使用小鼠汗腺作为模型，我们将研究汗水的分子变化 缺乏神经时发育过程中的腺干细胞，并进一步识别下游途径 在汗腺干细胞中，介导神经递质对干细胞维持的作用。通过 小鼠遗传学，免疫荧光共聚焦和轻板成像的联合使用，单细胞RNA 测序，荧光激活的细胞分选以及组织外植体和细胞培养系统，我们计划：1 研究汗腺发育和稳态期间的神经支配的影响； 2）剖析角色 汗管和汗腺发育中的特定神经递质； 3）了解机制 通过该钙介导汗腺干细胞命运的神经元控制。我们提出的研究完成 将提供有关神经系统影响汗腺的分子机制的新见解 在不同发育阶段的形态发生和细胞命运确定。此外，我们的结果将提供 开创性的洞察力对汗腺和神经如何共同开发成功能单位 为患有出汗缺乏症的患者促进再生疗法。