Role of autophagy in epidermal differentiation and homeostasis

自噬在表皮分化和稳态中的作用

• 批准号: 10543010
• 负责人: Cory L Simpson
• 金额: $ 13.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543010
• 关键词: Role; autophagy; epidermal; differentiation; homeostasis

Project Summary/Abstract Research: Epidermal homeostasis relies on two balanced processes: (1) mitotic keratinocytes in the basal layer must maintain healthy organelles despite damage due to aging and ultraviolet radiation in order to continually regenerate the upper layers and (2) post-mitotic cells in the outer layers must degrade organelles to form a compact, protective barrier for the body. The mechanisms governing these fundamental processes are poorly understood and this hampers our ability to restore epidermal barrier function in diseases like ichthyosis and atopic dermatitis and to prevent skin carcinogenesis and aging. My research will test the hypothesis that the epidermis relies upon autophagy pathways to drive organelle degradation as a constitutive process during cornification and in an inducible manner to repair damaged organelles. The proposed experiments apply super-resolution microscopy to image single organelle dynamics and degradation in live epidermis. The results will improve our understanding of the role of autophagy in epidermal homeostasis and differentiation and could suggest novel clinical uses of autophagy modulators for treatment of skin disease. Candidate: Cory Simpson earned his M.D. and Ph.D. from Northwestern Univ. in 2012, completed clinical dermatology training at the Univ. of Pennsylvania in 2016, and sees patients with blistering disease, barrier disorders, and skin cancer. Dr. Simpson is pursuing post-doctoral training in the lab of Dr. Erika Holzbaur, Ph.D., where he is coupling live organotypic human and murine skin with innovative microscopy approaches. The career development plan will allow Dr. Simpson to build on his training in keratinocyte biology to establish an independent research program defining mechanisms of organelle degradation during epidermal differentiation and upon environmental damage. Support from a K08 award will position Dr. Simpson to attain his goal of becoming an R01-funded investigator directing an academic lab focused on modulating keratinocyte organelle turnover to augment skin barrier function and prevent aging- and UV radiation-induced skin damage. Environment: The mentor, Dr. Holzbaur, is an NIH-funded Penn professor who provides (1) renowned expertise in organelle trafficking and autophagy in disease models, (2) unrivaled live cell imaging experience and state-of-the-art microscopes, and (3) exceptional mentorship of prior trainees including K08 recipients. Dr. Simpson’s application of Dr. Holzbaur’s toolkit to epidermis provides a natural independence from her focus on neurodegeneration. Dr. Holzbaur’s guidance will be complemented by a committee of new and established investigators with expertise in cutaneous biology, intravital microscopy, and physician-scientist training. The K08 proposal includes training in novel imaging techniques, new exposure to in vivo models, and coursework in advanced/quantitative microscopy. Penn offers an outstanding Dermatology faculty with opportunities to collaborate as well as NIAMS P30-supported core facilities for keratinocyte culture and histology, providing an optimal environment to support Dr. Simpson as he transitions to begin an independent research program.

项目总结/摘要 研究：表皮稳态依赖于两个平衡过程：（1）基底层中的有丝分裂角质形成细胞， 层必须保持健康的细胞器，尽管由于老化和紫外线辐射的损害， （2）外层的有丝分裂后细胞必须降解细胞器， 为身体形成一个紧密的保护屏障。控制这些基本过程的机制是 这阻碍了我们在鱼鳞病等疾病中恢复表皮屏障功能的能力 和特应性皮炎，并防止皮肤癌变和老化。我的研究将验证一个假设 表皮依赖于自噬途径来驱动细胞器降解， 角化和诱导的方式来修复受损的细胞器。建议的实验适用于 超分辨率显微镜成像单个细胞器动态和降解活表皮。结果 将提高我们对自噬在表皮稳态和分化中的作用的理解， 提出了自噬调节剂用于治疗皮肤病新的临床用途。 候选人：科里·辛普森获得了医学博士学位。和博士2012年从西北大学毕业，完成临床 2016年，他在宾夕法尼亚大学接受皮肤病学培训， 疾病和皮肤癌。辛普森博士正在Erika Holzbaur博士的实验室进行博士后培训， 哲学博士、在那里，他将活体器官型人类和小鼠皮肤与创新的显微镜方法结合起来。 职业发展计划将允许辛普森博士在角质形成细胞生物学方面的培训基础上， 一个独立的研究计划，确定表皮细胞器降解的机制， 差异化和环境破坏。来自K 08奖的支持将使辛普森博士获得 他的目标是成为一名R 01资助的研究人员，指导一个专注于调节角质形成细胞的学术实验室 细胞器周转，以增强皮肤屏障功能，防止老化和紫外线辐射引起的皮肤损伤。 环境：导师Holzbaur博士是NIH资助的宾夕法尼亚大学教授，他提供（1）著名的 疾病模型中细胞器运输和自噬的专业知识，（2）无与伦比的活细胞成像经验 和最先进的显微镜，以及（3）对之前学员（包括K 08学员）的出色指导。博士 辛普森将霍尔茨鲍尔博士的工具箱应用于表皮，这为她的重点提供了一种自然的独立性， 神经变性Holzbaur博士的指导将得到一个新成立的委员会的补充。 具有皮肤生物学、活体显微镜检查和医生-科学家培训方面专业知识的研究人员。的 K 08提案包括新型成像技术培训、体内模型新曝光和课程作业 高级/定量显微镜。宾夕法尼亚大学提供了一个优秀的皮肤科教师的机会， 合作以及NIAMS P30支持的角质细胞培养和组织学核心设施，提供了一个 最佳的环境，以支持辛普森博士，因为他过渡到开始一个独立的研究计划。