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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：
9107883
负责人：
Jeremy F Reiter
金额：
$ 56.72万
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107883
关键词：
Address Adult Affect Architecture Bardet-Biedl Syndrome Biochemical Biological Cells Characteristics Cilia Complex Congenital Abnormality Cues Defect Detection Development Diffusion Disease Distal Docking Embryo Event Genes Genetic Goals Holoprosencephaly Homeostasis Human Human body Joubert syndrome Link Malignant Neoplasms Maps Mediating Membrane Membrane Proteins Microscopy Microtubules Modeling Mus Mutation Names Nephronophthisis Neural tube Organelles Pattern Phenotype Plasma Polycystic Kidney Diseases Polydactyly Proteins Resolution Rest Role Signal Transduction Signaling Protein Smell Perception Structure Surface Syndrome System Testing Tissues Vision appendage base ciliopathy cilium biogenesis developmental disease gene interaction hedgehog signal transduction human disease innovation insight kinetosome live cell imaging mutant public health relevance research study smoothened signaling pathway tool

项目摘要

DESCRIPTION (provided by applicant): 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, only recently has it become clear 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 syndromes such as Meckel and Joubert syndromes, can underlie more common human diseases such as polycystic kidney disease, and are essential for the progression of some cancers. 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 the architecture of the transition zone and how it is disrupted by ciliopathy mutations will provide structural insights into the origins of ciliary signaling defects. Second, we will examine whether the transition zone regulates protein entry into the cilium, exit from the cilium, or acts as a diffusion barrier at the ciliary base. Understanding how different components impart different characteristics to the transition zone will help reveal how this gate controls ciliary composition. Third, we will examine how different complexes cooperate within the transition zone to support ciliogenesis and ciliary signaling. These experiments will help elucidate how mutations in different transition zone components result in different developmental phenotypes, both in mice and humans. By elucidating the mechanisms by which the transition zone controls ciliary composition, we will understand how the cell compartmentalizes this organelle to perform critical signaling functions during mammalian development.

描述(申请人提供)：人体内的许多细胞从其表面有一个单一的突起，称为初级纤毛。虽然初级纤毛的存在早在一个多世纪前就被认识到了，但直到最近才清楚地知道，它们在检测和解释重要的细胞间线索方面发挥着作用。其中一些信号，如刺猬信号，是胚胎模式和成人组织动态平衡的关键调节因素。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，初级纤毛缺陷会导致先天性综合征，如Meckel和Joubert综合征，可导致更常见的人类疾病，如多囊肾病，并对一些癌症的进展至关重要。为了在信号传递中发挥作用，初级纤毛需要保持与细胞周围部分不同的组成。我们确定过渡区，纤毛底部的一个区域，是纤毛组成的关键调节因素。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，考虑到过渡带是纤毛的一个复杂和高度结构化的区域，我们将确定它是如何构建的。确定过渡区的结构以及它是如何被纤毛病变突变破坏的，将为纤毛信号缺陷的起源提供结构性的见解。第二，我们将研究是否过渡区调节蛋白质进入纤毛、离开纤毛，或在纤毛底部起扩散屏障的作用。了解不同的成分如何赋予过渡区不同的特征将有助于揭示这个门是如何控制纤毛组成的。第三，我们将研究不同的复合体如何在过渡区内合作，以支持纤毛发生和纤毛信号。这些实验将有助于阐明不同过渡区成分的突变如何导致小鼠和人类不同的发育表型。通过阐明过渡区控制纤毛组成的机制，我们将了解细胞如何划分这个细胞器来执行哺乳动物发育过程中的关键信号功能。