Role of autophagy in epidermal differentiation and homeostasis

自噬在表皮分化和稳态中的作用

基本信息

批准号：
9977117
负责人：
Cory L Simpson
金额：
$ 17.23万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977117
关键词：
3-Dimensional Actins Aging Aminolevulinic Acid Atopic Dermatitis Autophagocytosis Autophagosome Award BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like Basal Cell Binding Biology Biotinylation Bulla CRISPR/Cas technology Calcium Cell Differentiation process Cell Proliferation Cells Chemicals Clinical Complement Confocal Microscopy Core Facility Coupling Cutaneous Degradation Pathway Dehydration Dermatology Development Plans Dimerization Disease Disease model Doctor of Medicine Doctor of Philosophy Dyes Endoplasmic Reticulum Environment Environmental Protection Epidermis Exposure to Faculty Family Funding Future Genetic Genetic Skin Diseases Goals Guanosine Triphosphate Phosphohydrolases Health Histology Homeostasis Human Image Impairment Injury Lasers Link Lysosomes Mediator of activation protein Membrane Proteins Mentors Mentorship Microscope Microscopy Mitochondria Mitotic Modeling Mus National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural regeneration Nerve Degeneration Normal tissue morphology Organelles Outer Mitochondrial Membrane PUVA Photochemotherapy Pathway interactions Patients Pennsylvania Phenotype Photosensitization Photosensitizing Agents Physicians Positioning Attribute Premalignant Cell Preparation Process Proteins Quality Control Quantitative Microscopy Reactive Oxygen Species Regulation Research Research Personnel Resolution Role Route Scientist Signal Transduction Skin Skin Aging Skin Cancer Skin Carcinogenesis Stratum Basale Stratum Lucidum System Testing Tissues Toxin Training UV Radiation Exposure Ultraviolet Rays Ultraviolet Therapy Undifferentiated United States National Institutes of Health Up-Regulation Water Work aged calcium indicator carcinogenicity career development confocal imaging experience experimental study genetic manipulation improved in vivo in vivo Model inhibitor/antagonist injured innovation intravital microscopy keratinization keratinocyte live cell imaging novel novel imaging technique optogenetics oxidative damage pathogen peroxisome post-doctoral training prevent professor programs ranpirnase receptor receptor function recruit repaired resilience response seal skin barrier skin disorder skin regeneration small hairpin RNA therapeutic evaluation trafficking ultraviolet damage

项目摘要

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.

项目摘要/摘要研究：表皮稳态取决于两个平衡的过程：（1）基本的有丝分裂角质形成细胞层必须由于老化和紫外线辐射而保持健康的细胞器目的地损害连续再生上层和（2）外层中的有丝分裂细胞必须降解细胞器形成一个紧凑的保护屏障。管理这些基本过程的机制是理解不佳，这妨碍了我们在疾病中恢复表皮屏障功能的能力和特应性皮炎，以防止皮肤致癌和衰老。我的研究将检验以下假设表皮依赖于自噬途径将细胞器降解作为构成过程的促进途径植物化并以诱导的方式修复受损的细胞器。提出的实验适用超分辨率显微镜图像实时表皮中的单细胞器动力学和降解。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，并且可以建议自噬调节剂治疗皮肤病的新型临床用途。候选人：科里·辛普森（Cory Simpson）获得了医学博士学位和博士学位。来自西北大学。 2012年，完成了临床大学的皮肤病学培训。 2016年宾夕法尼亚州的院士，并看到患有起泡疾病的患者疾病和皮肤癌。辛普森博士正在埃里卡·霍尔茨博尔博士的实验室进行博士后培训，博士学位，他正在使用创新的显微镜方法耦合活有机和鼠皮。职业发展计划将使辛普森博士能够在他在角质形成生物学方面的培训中建立一个独立的研究计划，定义了表皮期间细胞器降解机制分化和环境破坏。 K08奖的支持将使Simpson博士参加他成为由R01资助的研究人员的目标，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，并防止衰老和紫外线辐射引起的皮肤损伤。环境：导师Holzbaur博士是NIH资助的宾夕法尼亚州教授，他提供（1）（2）无与伦比的活细胞成像经验，在细胞器贩运和自噬方面的专业知识和最先进的显微镜，以及（3）包括K08接收者在内的先前受训者的特殊心态。博士辛普森（Simpson）将霍尔茨博尔（Holzbaur）工具包应用于表皮的应用提供了自然的独立性神经变性。 Holzbaur博士的指导将由一个新委员会完成研究人员具有皮肤生物学，浸润显微镜和身体科学训练方面的专业知识。这 K08提案包括新型成像技术的培训，新的体内模型接触和课程工作在高级/定量显微镜中。宾夕法尼亚州提供了出色的皮肤病学教师合作以及NIAMS P30支持角质形成细胞培养和组织学的核心设施，提供了一种最佳环境支持辛普森博士过渡开始独立研究计划。