Metabolic Regulation of Epidermal Homeostasis

表皮稳态的代谢调节

• 批准号: 9353177
• 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/9353177
• 关键词: Affect; Attention; Basal Cell; Biology; Biomass; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell Respiration; Cells; Characteristics; Development; Disease; Educational process of instructing; Educational workshop; Ensure; Epidermis; Epithelial; Equilibrium; Event; Exhibits; Family; Gene Expression; Generations; Genetic; Goals; Grant; Homeostasis; Impairment; Individual; Maintenance; Mediating; Mentors; Metabolic; Metabolism; Mitochondria; Molecular; Morphology; 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; TP53 gene; Time; Tissues; Training; Undifferentiated; Universities; Work; Wound Healing; Writing; career development; cell growth regulation; cell type; cofactor; collaborative environment; factor A; innovation; keratinocyte; keratinocyte differentiation; loss of function; metabolic phenotype; mitochondrial metabolism; new therapeutic target; notch protein; programs; public health relevance; responsible research conduct; skin disorder; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：为了维持其保护功能，表皮经历持续的稳态更新过程，其中增殖基底层内的细胞退出细胞周期并在它们穿过基底上表皮层时分化。与表皮角质形成细胞分化相关的形态学和遗传学变化被很好地描述。其他分子机制，如代谢重编程如何调节表皮稳态，尚未得到广泛研究。我们最近证明，氧化线粒体代谢和活性氧（ROS）的产生是促进角质形成细胞分化的关键调节因子。在基底表皮细胞中缺乏线粒体代谢和ROS生成的小鼠表现出表皮分化受损和增殖基底细胞水平增加。我们进一步证明了在线粒体产生的ROS作为关键的信号分子，其促进角质形成细胞分化所需的Notch信号事件的传播。在目前的提案中，我们将建立在我们最近报道的发现，大大扩展我们的理解，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在未分化状态。我们将把我们的注意力集中在p63，表皮发育和稳态所需的转录因子。p63属于已知是细胞代谢和ROS水平的调节剂的转录因子家族。我们将使用功能的获得和丧失研究来确定p63表达如何影响角质形成细胞糖酵解和氧化代谢。我们将仔细研究p63的表达如何影响通过生物合成途径的代谢物通量，以及p63的表达如何影响细胞ROS的水平。我们还将探讨已知的p63对Notch的抑制作用。我们将确定p63是否通过抑制ROS介导的信号传导来调节Notch。我们的研究将确定角质形成细胞在分化过程中的代谢变化，并确定代谢重编程在促进分化中的因果作用。本文提出的工作将为申请人提供发展成为独立皮肤生物学家所需的培训。该提案建立了申请人的现有优势，并通过表皮和上皮生物学的额外培训增加了他的能力。西北大学目前的协作环境将确保工作迅速有效地完成。重要的是，本提案中提供的培训将使申请人有时间利用西北大学提供的职业发展机会。这些包括研讨会在赠款写作，辅导，教学和负责任的研究行为。