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Regulation of Hedgehog-dependent proliferation by dynamic primary cilia

动态初级纤毛对刺猬依赖性增殖的调节

基本信息

批准号：
9754582
负责人：
Emily Kolenbrander Ho
金额：
$ 3.69万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754582
关键词：
Abnormal Cell Address Affect Biological Biological Assay Buffers Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Proliferation Cells Cerebellum Childhood Malignant Brain Tumor Cilia Congenital Abnormality Cytoplasmic Granules Data Development Disease Embryonic Development Equilibrium Erinaceidae Exhibits Fibroblasts G1 Phase G1/S Transition Genetic Screening Goals Growth Image Lead Link Malignant Neoplasms Microtubules Mitosis Modeling Molecular Neurons Normal Cell Organelles Organism Outcome Pathway interactions Phase Physiology Process Proliferating Receptor Activation Regulation Role Scientist Shapes Signal Transduction Structure Testing Therapeutic Time Tissues Training Ursidae Family Work base cell growth developmental disease event cycle hedgehog signal transduction improved live cell imaging medulloblastoma mouse model novel precursor cell small hairpin RNA small molecule inhibitor smoothened signaling pathway transcription factor

项目摘要

PROJECT SUMMARY The primary cilium is a microtubule-based signaling organelle with essential roles in many vertebrate tissues. Disruptions in cilium structure or function lead to a broad range of developmental disorders, including some cancers, revealing the critical function of cilia. Cilia are dynamic structures, undergoing assembly and disassembly during each cycle. Although cilium-based signaling can directly regulate the cell cycle, cilia function has been poorly studied in proliferating cells. Therefore, it is not understood how a transient organelle can regulate a sustained process such as proliferation. The goal of this proposal is to address this question in the context of Hedgehog (Hh) signaling, the classic example of a developmental pathway that requires the cilium for signal transduction. I propose to investigate the mechanisms of Hh-dependent proliferation in medulloblastoma (MB), the most frequent childhood brain cancer. MB cells require both cilia and Hh signaling for proliferation, and my preliminary work in an established cell culture model of MB provides evidence of a cilium cycle. Given that MB cells proliferate even though cilia are transient, my central hypothesis is that uncharacterized downstream mechanisms are necessary to buffer Hh-dependent proliferation against changing cilia. I will test this hypothesis with the following aims: 1) I will establish the relationship between Hh signaling and the cilium cycle. Using fluorescent live imaging and Hh signaling assays, I will determine how cilia and Hh signaling change throughout the cell cycle. 2) I will determine when signaling at cilia is necessary and sufficient for cell cycle progression, using live imaging of the cell cycle and small molecule inhibitors of Hh signaling. 3) I will use candidates from a large-scale genetic screen to identify new regulators of Hh-dependent proliferation that constitute novel components of the link between Hh signaling and proliferation as well as modulators of the Hh signaling pathway specific to the physiology of MB cells. The results will reveal how Hh signaling, cilia, and the cell cycle cooperate to drive MB growth, improving our understanding of cilium-based signaling in both normal and disease states.

项目总结