Metabolic Regulation of Epidermal Homeostasis

表皮稳态的代谢调节

• 批准号: 8750649
• 负责人: Robert Brian Hamanaka
• 金额: $ 8.48万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750649
• 关键词: Affect; Attention; Basal Cell; Biology; Biomass; Cell Cycle; Cell Proliferation; Cell Respiration; Cells; Characteristics; Development; Disease; Educational process of instructing; Educational workshop; Ensure; Environment; Epidermis; Epithelial; Equilibrium; Event; Exhibits; Family; Gene Expression; Generations; Genetic; Goals; Grant; Homeostasis; Individual; Maintenance; Mediating; Mentors; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Mutation; Oxidation-Reduction; Pathway interactions; Phenotype; Play; Population; Process; Production; Proliferating; Quality of life; Reactive Oxygen Species; Regenerative Medicine; Regulation; Reporting; Repression; Respiration; Role; Signal Transduction; Signaling Molecule; Skin; Stem cells; Stratum Basale; Time; Tissues; Training; Undifferentiated; Universities; Work; Wound Healing; Writing; career development; cell growth regulation; cell type; cofactor; innovation; keratinocyte; keratinocyte differentiation; loss of function; mtTF1 transcription factor; new therapeutic target; notch protein; programs; public health relevance; responsible research conduct; skin disorder; stem; transcription factor; treatment strategy

Project Summary In order to maintain its protective function, the epidermis undergoes a continual process of homeostatic renewal in which cells within the proliferative basal layer withdraw from the cell cycle and differentiate as they process through the suprabasal epidermal layers. The morphological and genetic changes associated with epidermal keratinocyte differentiation are well described. How other molecular mechanisms, such as metabolic reprogramming regulate epidermal homeostasis, have not been extensively studied. We recently demonstrated that oxidative mitochondrial metabolism and reactive oxygen species (ROS) production are critical regulators which promote keratinocyte differentiation. Mice which lacked mitochondrial metabolism and ROS generation in basal epidermal cells exhibited impaired epidermal differentiation and increased levels of proliferative basal cells. We further demonstrated that ROS produced at mitochondria act as critical signaling molecules which promote the propagation of Notch signaling events which are required for keratinocyte differentiation. In the current proposal, we will build on our recently-reported findings to dramatically extend our understanding of how the epidermal differentiation program regulates cellular metabolism to promote differentiation or to maintain basal cells in the undifferentiated state. We will focus our attention on p63, a transcription factor required for epidermal development and homeostasis. p63 belongs to a family of transcription factors which are known to be regulators of cellular metabolism and ROS levels. We will use gain and loss of function studies to determine how p63 expression affects keratinocyte glycolytic and oxidative metabolism. We will closely examine how p63 expression affects metabolite flux through biosynthetic pathways and how p63 expression affects levels of cellular ROS. We will also explore the known repressive effect that p63 has on Notch. We will determine if p63 regulates Notch through repression of ROS-mediated signaling. Our studies will determine how keratinocyte metabolism changes during differentiation and will determine the causal role that metabolic reprogramming plays in promoting differentiation. The work proposed herein will provide the applicant with the training required for development into an independent skin biologist. This proposal builds off of the existing strengths of the applicant and adds to his abilities with additional training in epidermal and epithelial biology. The collaborative environment present at Northwestern University will ensure that the work is completed expeditiously and efficiently. Importantly, the training provided for in this proposal will allow applicant time to take advantage of opportunities for career development available at Northwestern University. These include workshops in grant writing, mentoring, teaching, and responsible conduct of research.

项目摘要 为了维持其保护功能，表皮经历了一个持续的稳态过程， 再生，其中增殖基底层内的细胞退出细胞周期并随着它们的分化而分化 通过基底上表皮层的过程。形态学和遗传学上的变化与 表皮角质形成细胞的分化已有很好的描述。其他分子机制，如代谢 重编程调节表皮稳态，尚未被广泛研究。我们最近展示了 线粒体氧化代谢和活性氧（ROS）的产生是关键的调节因子， 其促进角质形成细胞分化。缺乏线粒体代谢和ROS产生的小鼠 在基底表皮细胞中表现出受损的表皮分化和增加的增殖基底细胞水平， 细胞我们进一步证明了线粒体产生的ROS作为关键的信号分子， 促进角质形成细胞分化所需的Notch信号传导事件的传播。 在目前的提案中，我们将以最近报告的发现为基础， 表皮分化程序如何调节细胞代谢以促进分化或 维持基底细胞处于未分化状态。我们将把注意力集中在转录因子p63上， 是表皮发育和体内平衡所必需的。p63属于转录因子家族， 已知是细胞代谢和ROS水平的调节剂。我们将使用函数的增益和损失 研究确定p63表达如何影响角质细胞糖酵解和氧化代谢。我们将 仔细研究p63表达如何通过生物合成途径影响代谢物通量，以及p63 表达影响细胞ROS的水平。我们还将探讨已知的p63对 缺口。我们将确定p63是否通过抑制ROS介导的信号传导来调节Notch。我们的研究 将决定角质形成细胞代谢在分化过程中的变化， 代谢重编程在促进分化中的作用。 本申请所建议的工作将为申请人提供发展成为 独立皮肤生物学家这个建议建立了申请人现有的优势，并增加了他的 在表皮和上皮生物学的额外培训的能力。当前的协作环境 西北大学将确保这项工作迅速有效地完成。重要的是 本建议书中提供的培训将使申请人有时间利用职业机会， 在西北大学的发展。其中包括赠款写作，指导， 教学和负责任的研究行为。