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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：
10906483
负责人：
Timothy Gershon
金额：
$ 24.33万
依托单位：
EMORY 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：
2018-06-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10906483
关键词：
Bcl xL regulated apoptosis cerebellar

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.

摘要这项资助将研究小脑发育和髓母细胞瘤中细胞凋亡的调节，以便获得关于小头畸形的发病机制和脑肿瘤治疗的新信息。髓母细胞瘤，最多儿童常见的恶性脑瘤，起源于出生后脑内增殖的小脑祖细胞。我们认为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，即使发育中的大脑容易受到生长障碍的影响，也使髓母细胞瘤容易受到辐射和化疗。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强，毒性小。我们已经证明，神经前体细胞和髓母细胞瘤细胞维持着一种死亡“状态，在这种状态下，促凋亡蛋白Bax被结构性地激活。这些细胞依赖于抗细胞凋亡阻止Bax诱导自发性细胞凋亡的蛋白质。在我们的初步研究中，我们删除了抗细胞凋亡的小脑祖细胞中的bclxl蛋白以确定小脑发育是否需要bclxl，以及是否有靶向 BCL-XL可抑制髓母细胞瘤的生长。我们发现，Bclxl缺失会导致小脑祖细胞死亡退出了细胞周期。这种效应阻碍了小脑的生长，但令人惊讶的是，并没有完全阻止髓母细胞瘤的发生在易患髓母细胞瘤的小鼠体内生长。同样令人惊讶的是，Bcl-XL缺失的祖细胞显示出增加扩散。基于这些发现，在目标1中，我们建议确定更多的与 BCL-XL调控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 Bc1-xl缺失的祖细胞具有促进增殖的作用，因为bclxl在分化过程中是必需的。 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发挥作用。在小脑祖细胞分化中的重要作用。我们将通过抑制Caspase来阻断细胞凋亡，然后确定bcl-xl是否是有氧糖酵解向氧化磷酸化转变所必需的祖细胞分化。在目标3中，我们将使用原代小鼠肿瘤模型来检查是否诱导髓母细胞瘤分化增强了Bclxl缺失的抗肿瘤作用。我们还将测试一种大脑功能，我们已经开发出纳米颗粒递送的bclxl抑制剂，作为一种潜在的髓母细胞瘤治疗方法。这些目标将展示bcl-xl如何在脑发育过程中调节祖细胞存活，并测试bclxl可以作为靶点的假设。以提高髓母细胞瘤的治疗水平。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval.

DOI：
10.1016/j.addr.2020.09.009
发表时间：
2020
期刊：
Advanced drug delivery reviews
影响因子：
16.1
作者：
Hwang D;Ramsey JD;Kabanov AV
通讯作者：
Kabanov AV

The intrinsically disordered SARS-CoV-2 nucleoprotein in dynamic complex with its viral partner nsp3a.

DOI：
10.1126/sciadv.abm4034
发表时间：
2022-01-21
期刊：
Science advances
影响因子：
13.6
作者：
Bessa LM;Guseva S;Camacho-Zarco AR;Salvi N;Maurin D;Perez LM;Botova M;Malki A;Nanao M;Jensen MR;Ruigrok RWH;Blackledge M
通讯作者：
Blackledge M

PRC2 disruption in cerebellar progenitors produces cerebellar hypoplasia and aberrant myoid differentiation without blocking medulloblastoma growth.