Regulation of the Hedgehog Pathway by new cilium proteins in Development and Disease

新纤毛蛋白在发育和疾病中对刺猬通路的调节

• 批准号: 10793882
• 负责人: Xuecai Ge
• 金额: $ 21.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793882
• 关键词: Biotinylation; Brain; Cell surface; Cells; Cilia; Congenital Abnormality; Defect; Development; Disease; Erinaceidae; Goals; In Vitro; Intervention; Label; Malignant Neoplasms; Methods; Molecular; Organelles; Pathway interactions; Proliferating; Protein Dynamics; Proteins; Proteomics; Regulation; Role; Signal Transduction; Signaling Protein; Time; Transducers; Transportation; developmental disease; hedgehog signal transduction; in vivo; innovation; nerve stem cell; neurodevelopment; novel; protein transport; receptor internalization; smoothened signaling pathway; tool; trafficking

PROJECT SUMMARY Defects in Hedgehog (Hh) signaling is widely implicated in various birth defects and cancers. The transduction of Hh signaling relies on the primary cilium, a miniature cell surface organelle known as the antenna of the cell. To activate Hh signaling, almost all protein transducers need to transit through the cilium. However, the molecular mechanisms of these protein transportation are not completely understood; and the signaling cascade within the cilium also remains unclear in the field. Our goal is to fill this gap with mechanistic studies of novel cilium proteins in the regulation of Hh signaling in vitro and in vivo. In preliminary studies, we have leveraged a new proximity-labeling tool and built an experimental platform to discovery new signaling proteins in the cilium with quantitative proteomics. We discovered surprising cilium localization of a molecule involved in receptor internalization during neural development. In this proposal, we aim to 1) decipher how the new cilium molecule control protein transport in the cilium during Hh signal activation; 2) determine its role in the Hh-controlled neural progenitor proliferation in the developing brain; and 3) apply the proximity biotinylation approach to identify new proteins involved in Smo trafficking and signaling during the time course of Hh activation. Our approach is innovative because it will reveal a new function of an old protein in the cilium during Hh transduction, and it employs a newly developed biotinylation tool to gain the systematic view of signaling proteins during Hh signaling activation. Upon completion, our study will shed light on long standing questions in the Hh pathway and may highlight new methods for the intervention of Hh related developmental disorders.

项目总结