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Glycolytic regulation of cerebellar development and medulloblastoma tumorigenesis

小脑发育和髓母细胞瘤肿瘤发生的糖酵解调节

基本信息

批准号：
9012118
负责人：
Timothy Gershon
金额：
$ 32.78万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-15 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9012118
关键词：
Anabolism Animals Apoptosis Brain Cell Cycle Cell physiology Cells Cerebellum Child Childhood Childhood Malignant Brain Tumor Clinical Cytoplasmic Granules Data Development Down-Regulation Enzymes Figs - dietary Freezing Genetic Genetically Engineered Mouse Glucose Glycolysis Growth Health Hexokinase 2 Human Label Life Link Lipids Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Metabolic Metabolism Mitogens Modeling Mus Mutation Neurons Nucleic Acids Nucleotides Operative Surgical Procedures Pathogenesis Pathway interactions Patients Pattern Phenotype Phosphorylation Physiological Processes Population Process Proliferating Pyruvate Pyruvate Kinase Regulation Role SHH gene Sampling Shapes Shunt Device Subgroup Testing Thinking Tissue Microarray Transgenic Mice Tumor Pathology Up-Regulation aerobic glycolysis base blood glucose regulation brain cell cancer therapy cell growth in vivo insight macromolecule medulloblastoma nerve stem cell neurodevelopment neurogenesis new therapeutic target postnatal prevent progenitor response sensor smoothened signaling pathway sugar targeted treatment tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): We propose to study the role of key metabolic regulators, AMPK, PkM2 and Hk2 in cerebellar development and medulloblastoma pathogenesis. Medulloblastoma, the most common malignant brain tumor in children, arises as a disruption of postnatal brain growth. We have found that aerobic glycolysis is integral to the physiologic process of progenitor proliferation in the postnatal cerebellum, and that up-regulation of Hk2 and PkM2 is required for this metabolic pattern. Importantly, inducing medulloblastoma formation in transgenic mice leads to prolonged aerobic glycolysis and aberrant expression of Hk2 and PkM2. We have previously demonstrated that conditional genetic deletion of Hk2 in cerebellar progenitors inhibits medulloblastoma formation in a primary mouse tumor model. Our preliminary evidence implicates activation of AMPK as the mechanism that blocks tumor growth when Hk2 is deleted. In contrast to Hk2, however, we found that deleting PkM2 promoted rather than inhibited tumor growth. These data demonstrate the potential of metabolic modulation to treat medulloblastoma but also the need for additional mechanistic understanding to appropriately target therapy. We now propose in our Aims: 1. To determine if Hk2-dependent glycolysis functions to prevent AMPK-mediated growth suppression during cerebellar development and tumorigenesis. 2. To determine if PkM2 promotes developmental and malignant growth by channeling intermediate products of aerobic glycolysis for biosynthetic processes. 3. To determine, patient-derived medulloblastoma samples, if Hk2 and PkM2 configure the metabolism of human medulloblastoma to promote growth. Through these aims, we will gain new insight into how metabolic processes mediated by Hk2, AMPK and PkM2 combine to regulate postnatal neurogenesis, become co-opted in medulloblastoma, and may be targeted for novel therapies.

描述（由申请人提供）：我们建议研究关键代谢调节因子AMPK、PkM2和Hk2在小脑发育和髓母细胞瘤发病机制中的作用。髓母细胞瘤是儿童中最常见的恶性脑肿瘤，是由于出生后大脑发育中断而引起的。我们已经发现，有氧糖酵解是不可或缺的生理过程中的祖细胞增殖在出生后的小脑，并上调Hk2和PkM2是需要这种代谢模式。重要的是，在转基因小鼠中诱导髓母细胞瘤形成导致有氧糖酵解延长和Hk2和PkM2的异常表达。我们先前已经证明，小脑祖细胞中Hk2的条件性遗传缺失抑制了原发性小鼠肿瘤模型中髓母细胞瘤的形成。我们的初步证据表明，AMPK的激活是Hk2缺失时阻断肿瘤生长的机制。然而，与Hk2相反，我们发现删除PkM2促进而不是抑制肿瘤生长。这些数据证明了代谢调节治疗髓母细胞瘤的潜力，但也需要额外的机制理解，以适当的靶向治疗。我们现在提出的目标是：1。确定在小脑发育和肿瘤发生过程中，Hk2依赖性糖酵解是否起阻止AMPK介导的生长抑制的作用。2.确定PkM2是否通过引导有氧糖酵解的中间产物用于生物合成过程来促进发育和恶性生长。3.确定患者源性髓母细胞瘤样品中Hk2和PkM2是否配置人髓母细胞瘤的代谢以促进生长。通过这些目标，我们将获得新的见解Hk2，AMPK和PKM2联合收割机介导的代谢过程如何调节出生后的神经发生，成为增选成神经管母细胞瘤，并可能成为新的治疗目标。