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Transition zone control of ciliary signaling

纤毛信号传导的过渡区控制

基本信息

批准号：
10466835
负责人：
Jeremy F Reiter
金额：
$ 58.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-18 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10466835
关键词：
Address Adult Affect Architecture Biochemical Biological Cell Line Cell Survival Cells Cilia Complex Congenital Abnormality Craniofacial Abnormalities Cues Data Defect Detection Development Embryo Face Genes Genetic Goals Hereditary Disease Homeostasis Human Human body Image In Vitro Interphase Cell Investigation Joubert syndrome Link Lipids Malignant Neoplasms Mediating Membrane Microscopy Modeling Molecular Mus Mutant Strains Mice Mutation Neural tube Organelles Organism Orthologous Gene PF4 Gene PKD2 protein Pattern Physiological Polycystic Kidney Diseases Positioning Attribute Production Prosencephalon Proteins Resolution Rest Role SHH gene Signal Transduction Smell Perception Structure Surface Testing Tissues Vision Work base ciliopathy cilium biogenesis craniofacial craniofacial development developmental disease digital experimental study hedgehog signal transduction human disease insight intercellular communication kinetosome mutant novel progenitor protein complex smoothened signaling pathway tool trafficking

项目摘要

Project summary/Abstract Many cells in the human body possess a singular projection from their surface called a primary cilium. Although the existence of primary cilia has been recognized for over a century, it has become clear only recently that they function in the detection and interpretation of important intercellular cues. Some of these cues, such as Hedgehog signals, are key regulators of embryonic patterning and adult tissue homeostasis. Consequently, defects in Hedgehog signaling can cause birth defects and some forms of cancer. Similarly, defects in primary cilia cause congenital ciliopathies such as Oro-facio-digital and Joubert syndromes, and can underlie more common human diseases such as polycystic kidney disease. To function in signaling, primary cilia need to maintain a different composition than surrounding parts of the cell. We identified the transition zone, a region of the ciliary base, as a critical regulator of ciliary composition. To understand how the transition zone controls which proteins localize to cilia, we will answer three complementary questions. First, given that the transition zone is a complex and highly structured region of the cilium, we will determine how it is built. Identifying how extra-ciliary protein complexes generate the transition zone will illuminate how mutations affecting non-ciliary proteins also cause ciliopathies. Second, we will examine how the transition zone regulates protein and lipid localization to the cilium. Understanding how different trafficking machines and their cargos use distinct mechanisms to cross the transition zone will help reveal how this gate controls ciliary protein composition. Additionally, we will build on recent data that the lipid composition of the ciliary membrane is specialized and essential for its signaling functions by examining how ciliary lipids enter the cilium and enriched there by the transition zone. These experiments will demonstrate how proteins regulate lipid composition to enable organelle-specific functions. Third, we will determine how the transition zone regulates craniofacial development. Many ciliopathies are associated with craniofacial defects, and our investigation of how transition zones function in facial patterning is revealing novel ways in which ciliary signaling regulates mammalian development. By elucidating the mechanisms by which the transition zone controls ciliary composition, we will help illuminate how the cell compartmentalizes this organelle to perform diverse signaling functions critical for development and physiological functioning.

项目概要/摘要人体内的许多细胞都有一个独特的突起，称为初级纤毛。虽然初级纤毛的存在已经被认识了超过一个世纪，最近，他们的功能在检测和解释重要的细胞间的线索。其中一些诸如Hedgehog信号的线索是胚胎模式和成体组织稳态的关键调节器。因此，Hedgehog信号的缺陷可能导致出生缺陷和某些形式的癌症。同样地，初级纤毛的缺陷引起先天性纤毛病，例如口面指综合征和Joubert综合征，并且可以导致了更常见的人类疾病，如多囊肾。为了在信号传导中发挥作用，初级纤毛需要保持与周围部分不同的组成。牢房我们确定了过渡区，睫状体基底的一个区域，作为睫状体的关键调节器，混合物.为了了解过渡区如何控制哪些蛋白质定位于纤毛，我们将回答三个互补的问题。首先，鉴于过渡区是纤毛的一个复杂且高度结构化的区域，我们将确定它是如何建造的。确定睫状体外蛋白复合物如何产生过渡区将阐明影响非纤毛蛋白的突变如何也引起纤毛病。其次，我们将研究过渡区如何调节蛋白质和脂质定位到纤毛。了解不同的贩运机器及其货物如何使用不同的机制穿越过渡区将有助于揭示这个门如何控制纤毛蛋白的组成。此外，我们将建立在最近的数据表明，睫状体膜的脂质成分是专门的，是其信号传导所必需的，通过检查纤毛脂质如何进入纤毛并通过过渡区在那里富集来发挥作用。这些实验将展示蛋白质如何调节脂质组成，使细胞器特异性功能。第三，我们将确定过渡区如何调节颅面发育。许多纤毛病变与颅面缺陷有关，我们对面部过渡区功能的研究模式化揭示了纤毛信号调节哺乳动物发育的新方式。通过阐明过渡区控制睫状体成分的机制，阐明细胞如何划分这个细胞器，以执行不同的信号功能，发育和生理功能。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynamic Remodeling of Membrane Composition Drives Cell Cycle through Primary Cilia Excision.

DOI：
10.1016/j.cell.2016.12.032
发表时间：
2017-01-12
期刊：
Cell
影响因子：
64.5
作者：
Phua SC;Chiba S;Suzuki M;Su E;Roberson EC;Pusapati GV;Schurmans S;Setou M;Rohatgi R;Reiter JF;Ikegami K;Inoue T
通讯作者：
Inoue T

Ciliary vesicle formation: a prelude to ciliogenesis.

DOI：
10.1016/j.devcel.2015.03.012
发表时间：
2015-03-23
期刊：
Developmental cell
影响因子：
11.8
作者：
Yee LE;Reiter JF
通讯作者：
Reiter JF

How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In.

DOI：
10.1016/j.cub.2018.03.010
发表时间：
2018-04-23
期刊：
Current biology : CB
影响因子：
0
作者：
Garcia G 3rd;Raleigh DR;Reiter JF
通讯作者：
Reiter JF

Endoderm development requires centrioles to restrain p53-mediated apoptosis in the absence of ERK activity.

DOI：
10.1016/j.devcel.2021.11.020
发表时间：
2021-12-20
期刊：
Developmental cell
影响因子：
11.8
作者：
Xie C;Abrams SR;Herranz-Pérez V;García-Verdugo JM;Reiter JF
通讯作者：
Reiter JF

Hedgehog signaling controls T cell killing at the immunological synapse.

DOI：
10.1126/science.1244689
发表时间：
2013-12-06
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
de la Roche M;Ritter AT;Angus KL;Dinsmore C;Earnshaw CH;Reiter JF;Griffiths GM
通讯作者：
Griffiths GM