Glycolytic regulation of cerebellar development and medulloblastoma tumorigenesis

 描述(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，发生于出生后大脑生长受阻的状态。我们发现有氧糖酵解是出生后小脑前体细胞增殖的生理过程中不可或缺的一部分，这种代谢模式需要Hk2和PKM2的上调。重要的是，在转基因小鼠中诱导髓母细胞瘤的形成会导致长时间的有氧糖酵解和Hk2和PKM2的异常表达。我们之前已经证明，在小脑祖细胞中有条件的Hk2基因缺失可以抑制小鼠原发肿瘤模型中髓母细胞瘤的形成。我们的初步证据表明，当Hk2缺失时，AMPK的激活可能是阻止肿瘤生长的机制。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，但也需要更多的机制了解以适当的靶向治疗。我们现在的目标是：1.确定Hk2依赖的糖酵解是否在小脑发育和肿瘤发生过程中起到防止AMPK介导的生长抑制的作用。2.确定PKM2是否通过将好氧糖酵解中间产物引导到生物合成过程来促进发育和恶性生长。3.确定患者来源的髓母细胞瘤样本中，Hk2和PKM2是否配置了人髓母细胞瘤的代谢以促进生长。通过这些目标，我们将对Hk2、AMPK和PKM2介导的代谢过程如何结合来调节出生后神经发生、成为髓母细胞瘤的增选机制以及可能成为新的治疗靶点有新的认识。

 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.