Role of Primary Cilia During Epidermal Morphogenesis

初级纤毛在表皮形态发生过程中的作用

• 批准号: 8494575
• 负责人: Ellen Ezratty
• 金额: $ 9.58万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494575
• 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; 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

DESCRIPTION (provided by applicant): 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 post-doctoral 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 proliferatin 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 microtubule-based cellular "antenna" that can sense the extracellular environment, transmit developmental signals, and influence cell-cycle progression. Dysfunctional cilia result in human genetic diseases referred to as "ciliopathies", and in diseases that precipitate the transition fro 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 well-characterized in other model systems, the molecular mechanisms underlying cilia-mediated 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 f known ciliary trafficking mechanisms regulate the localization, activation, and function of Notch signaling components during epidermal differentiation. 3) Identify the cell-cycle regulatory factors that function in cilia-mediated control of epidermal proliferation during skin differentiaton and hair follicle morphogenesis.

描述（由申请人提供）：我的研究生和博士后训练给我留下了深刻的印象，让我了解基本细胞生物学过程的分子机制及其对人类疾病病理的贡献的重要性。当我准备过渡到一个独立的研究职位时，我被迫获得额外的技术技能和教育，这将使我能够获得研究自主权，并开发一个创新的基础研究项目，解决细胞和发育生物学的基本问题。作为洛克菲勒大学（The Rockefeller University）伊莱恩·富克斯（Elaine Fuchs）的博士后研究员，我发现自己处在一个理想的环境中，这将促进我作为一名专业人士的持续成长