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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：
9805013
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/9805013
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 Physicians Positioning Attribute Premalignant 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 cancer cell 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 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.

项目总结/文摘