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：
10650345
负责人：
Cory L Simpson
金额：
$ 16.55万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10650345
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 Cells Chemicals Clinical Collaborations 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 Gene Targeting Genetic Genetic Skin Diseases Goals Guanosine Triphosphate Phosphohydrolases Health Histology Homeostasis Human Image Impairment Injury Invaded Lasers Link Lysosomes Mediator 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 Photosensitizing Agents Physicians Positioning Attribute Premalignant Cell Preparation Process Proteins Quality Control Quantitative Microscopy Reactive Oxygen Species Recycling Regulation Research Research Personnel Role Route Scientist Signal Transduction Skin Skin Aging Skin Cancer Skin Carcinogenesis Stratum Basale Stratum Lucidum System Testing Tissues Toxin Training UV Radiation Exposure UV induced Ultraviolet Rays Ultraviolet Therapy Undifferentiated United States National Institutes of Health Up-Regulation Work aged calcium indicator carcinogenicity career development confocal imaging experience experimental study genetic manipulation improved in vivo in vivo Model inhibitor injured innovation intravital microscopy keratinization keratinocyte live cell imaging novel novel imaging technique optogenetics oxidative damage pathogen peroxisome post-doctoral training postmitotic prevent professor programs receptor receptor function recruit repaired resilience response seal skin barrier skin damage skin disorder skin regeneration small hairpin RNA superresolution microscopy 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.

项目概要/摘要研究：表皮稳态依赖于两个平衡过程：（1）基底层的有丝分裂角质形成细胞尽管由于老化和紫外线辐射而受损，细胞层仍必须保持健康的细胞器，以便不断地再生上层，并且（2）外层的有丝分裂后细胞必须降解细胞器以为身体形成一个紧凑的保护屏障，控制这些基本过程的机制是。人们对此知之甚少，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以及预防皮肤癌和衰老我的研究将检验以下假设：表皮依靠自噬途径来驱动细胞器降解作为一个组成过程角化并以诱导方式修复受损的细胞器。所提出的实验适用。超分辨率显微镜对活表皮中的单个细胞器动力学和降解进行成像。将提高我们对自噬在表皮稳态和分化中作用的理解，并可能提出自噬调节剂治疗皮肤病的新临床用途。候选人：Cory Simpson 于 2012 年获得西北大学临床医学博士学位。 2016 年在宾夕法尼亚大学接受皮肤科培训，见到患有水疱病、障碍的患者辛普森博士正在埃里卡·霍尔兹鲍尔博士的实验室进行博士后培训，博士期间，他正在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。职业发展计划将使辛普森博士能够以他在角质形成细胞生物学方面的培训为基础，建立一个独立的研究项目，定义了表皮细胞降解的机制差异化和环境破坏的支持将使辛普森博士能够实现这一目标。他的目标是成为一名 R01 资助的研究人员，领导一个专注于调节角质形成细胞的学术实验室细胞器更新，增强皮肤屏障功能，防止衰老和紫外线辐射引起的皮肤损伤。环境：导师 Holzbaur 博士是一位 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方面的专业知识，(2) 无与伦比的活细胞成像经验和最先进的显微镜，以及（3）对包括 K08 获得者在内的先前学员的出色指导。辛普森将 Holzbaur 博士的工具包应用于表皮，使她自然地独立于她对皮肤的关注 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、活体显微镜和医师科学家培训方面专业知识的研究人员。 K08 提案包括新颖成像技术的培训、体内模型的新接触以及课程作业宾夕法尼亚大学拥有先进/定量显微镜专业，为优秀的皮肤科教师提供了机会与 NIAMS P30 支持的角质形成细胞培养和组织学核心设施进行合作，提供为辛普森博士转型开始独立研究项目提供支持的最佳环境。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Actin cables and comet tails organize mitochondrial networks in mitosis.

肌动蛋白线和彗尾在有丝分裂中组织线粒体网络。

DOI：
发表时间：
2021
期刊：
影响因子：
64.8
作者：
Moore, Andrew S;Coscia, Stephen M;Simpson, Cory L;Ortega, Fabian E;Wait, Eric C;Heddleston, John M;Nirschl, Jeffrey J;Obara, Christopher J;Guedes;Boecker, C Alexander;Chew, Teng;Theriot, Julie A;Lippincott
通讯作者：
Lippincott

Autoimmune bullous disease in skin of color: A case series.

有色皮肤的自身免疫性大疱病：病例系列。