Defining the relationship of ciliary Arl13b and Smoothened

定义睫状 Arl13b 和 Smoothened 的关系

基本信息

批准号：
9760854
负责人：
Eduardo D. Gigante
金额：
$ 4.5万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2022-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760854
关键词：
Affect Alleles Binding Biological Assay Brain Cilia Complex Congenital Abnormality Data Development Digit structure Disease Embryo Embryonic Development Engineering Erinaceidae Exencephalies Face G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetic Genetic Transcription Guanosine Triphosphate Phosphohydrolases Hand Holoprosencephaly Joubert syndrome Knowledge Lead Ligands Limb structure Link Malignant Neoplasms Measures Methods Modeling Mus Mutant Strains Mice Mutation Neural tube Organelles Pathway interactions Pattern Phenotype Physiological Point Mutation Positioning Attribute Pregnancy Process Proteins Publishing Regulation Research Role SHH gene Severities Signal Pathway Signal Transduction Skeleton Sonic Hedgehog Pathway Spinal Cord Spinal Dysraphism Testing Time Training Transducers base bone ciliopathy experimental study improved inhibitor/antagonist knock-down neural patterning neurodevelopment novel response smoothened signaling pathway tool transcription factor

项目摘要

PROJECT SUMMARY Mutations to the Hedgehog signaling pathway are known to cause common birth defects. Here, I propose studying how the components of the Hedgehog pathway are regulated by the proteins of the primary cilium. We hope that by studying where these pathways intersect we can better understand how the two processes interact together in the healthy and disease states. The Hedgehog signaling pathway is known to influence a variety of aspects of early development, including the brain, spinal cord, and skeleton of the face, limbs and hands. Strangely, this pathway relies on a poorly understood cellular organelle called the primary cilium. I propose that the key to better understanding pathway function is my studying how the pathway’s components are regulated by the primary cilium and its ciliary proteins. I have hypothesized that a ciliary protein Arl13b is necessary for the full activation of Smoothened, the activator of the Hedgehog signaling cascade. The specific aims of this project are 1) to use a newly invented assay to measure Smoothened activation in the context of ciliary and non-ciliary Arl13b and 2) to characterize the physiological impact ciliary and non-ciliary Arl13b has on Smoothened activation in the developing mouse embryo. Through these methods, I aim to define the role of Arl13b in Smoothened activation and strive to better understand the link between the Hedgehog pathway and the primary cilium.

项目概要已知刺猬信号通路的突变会导致常见的出生缺陷。研究初级纤毛蛋白如何调节 Hedgehog 通路的组成部分。我们希望通过研究这些途径的交叉点，我们可以更好地理解这两个过程是如何发生的已知 Hedgehog 信号通路在健康和疾病状态下相互作用。早期发育的各个方面，包括大脑、脊髓、面部骨骼、四肢和奇怪的是，这条途径依赖于一种人们知之甚少的细胞器，即初级纤毛 I。提出更好地理解通路功能的关键是我研究通路的组成部分如何受初级纤毛及其纤毛蛋白的调节我重新认识到纤毛蛋白 Arl13b 是完全激活 Smoothened 所必需的，它是 Hedgehog 信号级联的特定激活剂。该项目的目标是 1) 使用新发明的测定法来测量平滑激活纤毛和非纤毛 Arl13b 和 2) 表征纤毛和非纤毛 Arl13b 的生理影响通过这些方法，我的目的是确定发育中的小鼠胚胎的平滑激活的作用。 Arl13b 处于平滑激活状态，并努力更好地理解 Hedgehog 通路与初级纤毛。