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Role of Primary Cilia During Epidermal Morphogenesis

初级纤毛在表皮形态发生过程中的作用

基本信息

批准号：
8897563
负责人：
Ellen Ezratty
金额：
$ 24.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897563
关键词：
Address Affect Basic Science Biochemical Biological Models Biological Process Cancer Etiology Cell Communication Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell division Cells Cilia Cues Data Defect Development Developmental Biology Developmental Cell Biology Differentiation and Growth Disease Education Electron Microscopy Embryo Environment Epidermis Epithelial Equilibrium Fostering Funding Future Gap Junctions Growth Guanosine Triphosphate Phosphohydrolases Hair follicle structure Hereditary Disease Homeostasis Human Genetics Image In Vitro Indirect Immunofluorescence Individual Laboratories Malignant Neoplasms Mediating Mentors Microtubules Molecular Morphogenesis Mus Mutate Natural regeneration Normal tissue morphology Pathology Play Polycystic Kidney Diseases Positioning Attribute Postdoctoral Fellow Process Proteins Reliance Renal carcinoma Research Research Personnel Resolution Role Scientist Signal Pathway Signal Transduction Skin Stem cells Structure Technical Expertise Testing Time Tissue Differentiation Tissues Training United States National Institutes of Health Universities base body system ciliopathy experience extracellular human disease in vivo innovation intercellular communication interest keratinocyte mutant notch protein novel post-doctoral training programs protein transport regenerative response skills skin regeneration small hairpin RNA smoothened signaling pathway stem cell population trafficking

项目摘要

Project Summary My graduate and postdoctoral training has impressed upon me the importance of understanding the molecular mechanisms of basic cell biological processes and their contribution to pathologies underlying human disease. As I prepare to transition into an independent research position, I’m compelled to acquire the additional technical skills and education that will enable me to gain research autonomy and develop an innovative basic research program addressing fundamental questions in cell and developmental biology. As a postdoctoral fellow with Elaine Fuchs at The Rockefeller University, I find myself in an ideal environment that will foster my continual growth as a scientist and mentor, and enable me to acquire additional technical expertise and generate research materials that will facilitate my future independent research endeavors. One fundamental question in developmental biology is how an individual cell may sense its environment to transmit extracellular signals that control cell signaling and proliferation during tissue morphogenesis. This activation of developmental cell signaling pathways must be temporally and spatially regulated in order to balance tissue growth with differentiation. When this goes awry during normal tissue homeostasis, proliferative conditions such as polycystic kidney disease (PKD) and cancer arise. The long term objective of my proposal is to understand how primary cilia temporally and spatially regulate developmental signaling and cell proliferation during epidermal morphogenesis. The primary cilium is a microtubulebased cellular “antenna” that can sense the extracellular environment, transmit developmental signals, and influence cellcycle progression. Dysfunctional cilia result in human genetic diseases referred to as “ciliopathies”, and in diseases that precipitate the transition from cellular quiescence to proliferation, such as PKD and cancer. Preliminary data indicate that primary cilia play at least two temporally and spatially distinct roles in balancing growth and differentiation during skin development: a novel, early role in epidermis, whose morphogenesis relies upon Notch signaling; and a later role in hair follicles, reliant upon Sonic Hedgehog (Shh) signaling. Although the reliance of Shh signaling on cilia is expected and wellcharacterized in other model systems, the molecular mechanisms underlying ciliamediated control of Notch signaling and cell proliferation during epidermal morphogenesis are unknown. I hypothesize that spatial and temporal activation of Notch signaling and epidermal proliferation are directly regulated by primary cilia during normal skin development. To test this central hypothesis I will 1) Characterize the spatial and temporal localization and dynamics of notch signaling components at the primary cilia during cell division and differentiation. 2) Determine if known ciliary trafficking mechanisms regulate the localization, activation, and function of Notch signaling components during epidermal differentiation. 3) Identify the cellcycle regulatory factors that function in ciliamediated control of epidermal proliferation during skin differentiation and hair follicle morphogenesis.

项目总结