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: 8353816
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353816
• 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. PUBLIC HEALTH RELEVANCE: The primary cilium is a cellular "antenna" that can sense the extracellular environment, transmit developmental signals, and influence cell-cycle progression. Non-functional cilia contribute to proliferative diseases such as polycystic kidney disease and cancer, and cause a spectrum of genetic diseases called "ciliopathies", which affect numerous organ systems and tissues. The diversity of organ systems affected in these human genetic diseases highlight the necessity to develop tissue-specific model systems, such as the skin, to study the function of primary cilia during differentiation, tissue morphogenesis, cell proliferatio and cancer.

描述（由申请人提供）：我的研究生和博士后培训给我留下了深刻的印象，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学的贡献的重要性。当我准备过渡到一个独立的研究职位，我不得不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计划，解决细胞和发育生物学的基本问题。作为洛克菲勒大学伊莱恩·富克斯的博士后研究员，我发现自己处于一个理想的环境中，这将促进我作为一个 科学家和导师，使我能够获得额外的技术专长，并产生研究材料，这将有助于我未来的独立研究工作。发育生物学中的一个基本问题是个体细胞如何感知其环境以传递细胞外信号，从而在组织形态发生期间控制细胞信号传导和增殖。 发育细胞信号通路的这种激活必须在时间和空间上进行调节，以平衡组织生长与分化。当这在正常组织稳态期间出错时，就会出现增殖性疾病，如多囊肾病（PKD）和癌症。我的建议的长期目标是了解初级纤毛如何在时间和空间上调节表皮形态发生过程中的发育信号和细胞增殖。初级纤毛是一种基于微管的细胞“天线”，可以感知细胞外环境，传递发育信号，并影响细胞周期进程。纤毛功能障碍导致称为“纤毛病”的人类遗传疾病，以及导致细胞从静止到增殖的转变的疾病，如PKD和癌症。 初步数据表明，初级纤毛在平衡生长和发育方面至少起着两种时间和空间上不同的作用， 在皮肤发育过程中的分化：一个新的，早期的作用在表皮，其形态依赖于Notch信号传导;和后期的作用在毛囊，依赖于Sonic Hedgehog（Shh）信号传导。虽然Shh信号对纤毛的依赖是预期的，并且在其他模型系统中得到了很好的表征，但表皮形态发生期间纤毛介导的Notch信号和细胞增殖控制的分子机制尚不清楚。我推测，在正常皮肤发育过程中，Notch信号传导和表皮增殖的空间和时间激活直接受初级纤毛调节。为了验证这一中心假设，我将1）表征在细胞分裂和分化过程中初级纤毛上notch信号成分的空间和时间定位和动力学。 2)确定已知纤毛运输机制调节表皮分化过程中Notch信号组分的定位、激活和功能。3)确定在皮肤分化和毛囊形态发生过程中纤毛介导的表皮增殖控制中起作用的细胞周期调节因子。 公共卫生相关性：初级纤毛是细胞的“天线”，可以感知细胞外环境，传递发育信号，并影响细胞周期进程。非功能性纤毛有助于增殖性疾病，如多囊肾病和癌症，并引起一系列称为“纤毛病”的遗传疾病，其影响许多器官系统和组织。这些人类遗传性疾病中受影响的器官系统的多样性突出了开发组织特异性模型系统（例如皮肤）的必要性，以研究初级纤毛在分化、组织形态发生、细胞增殖和癌症期间的功能。