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Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment

Bcl-xL 调节小脑发育和髓母细胞瘤治疗中的细胞凋亡

基本信息

批准号：
10462482
负责人：
Timothy Gershon
金额：
$ 9.54万
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：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-06-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462482
关键词：
Acute Apoptosis Apoptosis Regulation Gene Apoptotic BAX gene BCL1 Oncogene BCL2L1 gene BCL2L11 gene BIM Bcl-2-binding protein Bax protein Brain Brain Diseases Brain Neoplasms Caspase Cell Cycle Cell Death Cell Respiration Cell Survival Cells Cerebellum Cessation of life Chemotherapy and/or radiation Childhood Malignant Brain Tumor Chronic Complement Congenital cerebellar hypoplasia Cytoplasmic Granules DNA Damage Data Dependence Development Energy Metabolism Equilibrium Failure Formulation Gatekeeping Genetic Genotoxic Stress Glucose Glycolysis Grant Growth Growth Disorders HK2 gene Homologous Gene Impairment Individual Intervention Link MCL1 gene Malignant - descriptor Malignant neoplasm of brain Mediating Metabolic Microcephaly Mitochondria Modeling Molecular Conformation Mus Necrosis Normal Cell Oxidative Phosphorylation Pathogenesis Pediatric Neoplasm Pharmacology Play Process Proliferating Proteins Radiation Radiation Tolerance Radiation therapy Recurrence Regulation Resistance Role SHH gene Signal Transduction Subgroup System Testing Toxic effect Transgenic Organisms Work aerobic glycolysis antitumor effect base bcl-xlong protein improved in vivo inhibitor insight medulloblastoma mimetics nanoparticle nanoparticle delivery nerve stem cell neurogenesis novel postnatal preclinical study prevent pro-apoptotic protein progenitor response response to injury targeted treatment tumor tumor growth

项目摘要

ABSTRACT This grant will investigate the regulation of apoptosis during cerebellar development and in medulloblastoma, in order to gain new information on the pathogenesis of microcephaly and on brain tumor treatment. Medulloblastoma, the most common malignant brain tumor in children, arises from cerebellar progenitors that proliferate in the postnatal brain. We propose that cerebellar progenitors and medulloblastoma cells share a specialized mechanism of apoptosis regulation that makes the developing brain susceptible to growth failure and also makes medulloblastoma vulnerable to radiation and chemotherapy. Directly targeting this apoptosis mechanism may be a new way to treat medulloblastoma with greater efficacy and reduced toxicity. We have shown that neural progenitors and medulloblastoma cells maintain a “primed-for- death” state, in which the pro-apoptotic protein BAX is constitutively activated. These cells depend on anti-apoptotic proteins to prevent BAX from inducing spontaneous apoptosis. In our preliminary studies, we deleted the anti-apoptotic protein Bcl-xL in cerebellar progenitors to determine if BCL-xL is required for cerebellar development, and if targeting BCL-xL can impair medulloblastoma growth. We found that Bcl-xL deletion caused cerebellar progenitors to die as they exited the cell cycle. This effect blocked cerebellar growth, but surprisingly did not fully prevent medulloblastomas from growing in medulloblastoma-prone mice. Also surprising was that Bcl-xL-deleted progenitors showed increased proliferation. Based on these findings, in Aim 1 we propose to identify additional apoptosis regulators that work with BCL-xL to govern the survival of cerebellar progenitors and medulloblastoma cells. In Aim 2, we will test the hypothesis that Bcl-xL-deleted progenitors have increased proliferation because BCL-xL is required for the process of differentiation. BCL-xL has been implicated in mitochondrial function, and we have previously shown that oxidative metabolism plays an essential role in the differentiation of cerebellar progenitors. We will block apoptosis by Caspase inhibition and then determine whether BCL-xL is required for the transition from aerobic glycolysis to oxidative phosphorylation during progenitor differentiation. In Aim 3, we will use a primary mouse tumor model to examine whether inducing differentiation in medulloblastoma increases the anti-tumor effect of Bcl-xL deletion. We will also test a brain-permeant, nanoparticle-delivered BCL-xL inhibitor that we have developed as a potential medulloblastoma therapy. These Aims will show how BCL-xL regulates progenitor survival during brain growth, and test the hypothesis that BCL-xL can be targeted to improve medulloblastoma therapy.

摘要该基金将研究小脑发育和髓母细胞瘤中细胞凋亡的调节，获得关于小头畸形发病机制和脑肿瘤治疗的新信息。髓母细胞瘤，最儿童常见的恶性脑肿瘤，起源于出生后大脑中增殖的小脑祖细胞。我们提出小脑祖细胞和髓母细胞瘤细胞共享一种特殊的凋亡调节机制，使发育中的大脑容易生长失败，也使髓母细胞瘤容易受到辐射，化疗直接靶向这种凋亡机制可能是治疗髓母细胞瘤的一种新方法，功效和降低的毒性。我们已经证明，神经祖细胞和髓母细胞瘤细胞维持一个“启动- 死亡”状态，其中促凋亡蛋白BAX被组成性激活。这些细胞依赖于抗凋亡蛋白质以防止BAX诱导自发凋亡。在我们的初步研究中，我们删除了抗凋亡基因，小脑祖细胞中的蛋白Bcl-xL，以确定BCL-xL是否是小脑发育所需的，以及是否靶向 BCL-xL可损害髓母细胞瘤生长。我们发现Bcl-xL缺失导致小脑祖细胞死亡，退出细胞周期。这一作用阻断了小脑的生长，但令人惊讶的是，在有髓母细胞瘤倾向的小鼠体内生长。同样令人惊讶的是，Bcl-xL缺失的祖细胞显示出增加的细胞凋亡。增殖基于这些发现，在目标1中，我们提出鉴定与细胞凋亡相关的其他凋亡调节因子。 BCL-xL控制小脑祖细胞和髓母细胞瘤细胞的存活。在目标2中，我们将检验假设 Bcl-xL缺失的祖细胞具有增加的增殖，因为Bcl-xL是分化过程所需的。 BCL-xL与线粒体功能有关，我们之前已经证明氧化代谢在线粒体功能中起着重要作用。在小脑祖细胞分化中起重要作用。我们将通过抑制半胱天冬酶来阻断细胞凋亡，确定BCL-xL是否需要从有氧糖酵解到氧化磷酸化的过渡，祖细胞分化在目标3中，我们将使用原发性小鼠肿瘤模型来检查是否诱导肿瘤细胞凋亡。在髓母细胞瘤中的分化增加了Bcl-xL缺失的抗肿瘤作用。我们还将测试一种脑渗透，我们已经开发了一种纳米颗粒递送的BCL-xL抑制剂作为潜在的髓母细胞瘤治疗。这些目标将显示BCL-xL如何在大脑生长过程中调节祖细胞存活，并测试BCL-xL可以靶向的假设来改善髓母细胞瘤的治疗