Regulation of Shh Signaling by Cellular Energetics

细胞能量学对 Shh 信号传导的调节

基本信息

批准号：
10001606
负责人：
CHIN CHIANG
金额：
$ 40.02万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001606
关键词：
5&apos -AMP-activated protein kinase Autophagocytosis Cell Cycle Cell Differentiation process Cell Maintenance Cell Proliferation Cells Cerebellar Neoplasms Cerebellum Childhood Childhood Brain Neoplasm Consumption Cytoplasmic Granules Degradation Pathway Development Erinaceidae Fatty Acids Fibroblasts Foundations Gli2 protein Homeostasis Human Light Lysosomes Malignant Neoplasms Metabolism Mus Neoplasms Neurons Pathway interactions Pattern Play Process Protein Biosynthesis Protein Kinase Regulation Role Signal Pathway Signal Transduction Sterols Subfamily lentivirinae Testing Tissues Transgenic Mice cancer therapy cell growth granule cell in vivo inhibitor/antagonist insight lipid biosynthesis medulloblastoma multicatalytic endopeptidase complex neoplastic cell new therapeutic target novel postnatal development postnatal period precursor cell response sensor stem cells tumor tumor initiation tumorigenesis

项目摘要

Project Summary: The Shh pathway plays critical roles in development, stem cell maintenance and tissue homeostasis. Deregulated Shh signaling during cerebellar development causes medulloblastoma, the most common pediatric brain tumors in childhood with presumed cellular origin in granule cell precursors (GCPs). During postnatal development, GCPs undergo rapid and transient proliferation in the outer external granule layer (EGL) in response to Shh signaling before differentiating and migrating inward to become granule neurons. Persistent Shh signaling counters this stereotypic developmental pattern, resulting in disrupted differentiation and prolonged stay of GCPs in the outer EGL where cerebellar neoplasm is thought to initiate. Therefore, elucidating the mechanism by which CGP proliferation and differentiation are regulated is important to our understanding of cerebellar tumorigenesis. Deregulated cellular growth and proliferation are hallmarks of neoplasms that entail energy-consuming anabolic processes such as protein synthesis and lipogenesis. These anabolic processes are highly regulated and subject to stringent control by cellular energy sensors. The key energy sensor that is activated under condition of energy depletion is AMP-activated protein kinase (AMPK). We discovered that AMPK is a potent inhibitor of Shh signaling in GCPs and primary medulloblastoma cells. Moreover, AMPK is selectively activated in the inner EGL of the developing cerebellum where Shh signaling is downregulated and GCPs have begun differentiating. These observations suggest that AMPK may play a critical role in modulating Shh signaling in GCPs for differentiation, proliferation and tumorigenesis. We will test this hypothesis by three aims: 1) Elucidate the mechanism by which AMPK activation antagonizes Shh pathway activity; 2) Determine the role of AMPK in modulating GCP proliferation and differentiation in vivo; 3) Determine the effect of AMPK activation in Shh-driven medulloblastoma in vivo.

项目摘要： SHH途径在发育，干细胞维持和组织稳态中起关键作用。小脑发育过程中放松管制的SHH信号传导导致髓母细胞瘤，最常见儿童期的小儿脑肿瘤在颗粒细胞前体（GCP）中假定细胞起源。期间产后发育，GCP在外部颗粒层中经历快速和短暂的增殖（EGL）在区分和向内迁移以成为颗粒神经元之前应对SHH信号传导。持续的SHH信号反驳了这种刻板印象的发展模式，导致分化的破坏 GCP在外部EGL中长时间停留，而小脑肿瘤被认为是启动的。所以，阐明CGP增殖和分化的机制对我们的对小脑肿瘤发生的理解。失调的细胞生长和增殖是肿瘤需要耗尽能量的合成代谢过程，例如蛋白质合成和脂肪生成。这些合成代谢过程受到高度调节，并受细胞能传感器的严格控制。钥匙在能量消耗条件下被激活的能量传感器是AMP激活的蛋白激酶（AMPK）。我们发现AMPK是GCP和原代髓母细胞细胞中SHH信号传导的有效抑制剂。此外，AMPK在发育中的小脑的内部EGL中有选择地激活SHH信号是下调和GCP已经开始区分。这些观察结果表明AMPK可能会发挥在调节GCP中的SHH信号传导中的关键作用以分化，增殖和肿瘤发生。我们将测试该假设通过三个目的：1）阐明AMPK激活拮抗SHH的机制途径活动； 2）确定AMPK在调节体内GCP增殖和分化的作用； 3）确定AMPK激活在体内SHH驱动的髓母细胞瘤中的影响。