Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
批准号:
10906483
负责人:
Timothy Gershon
金额:
$24.33万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-06-01 至 2024-04-30
中文摘要
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可以损害髓母细胞瘤的生长。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
英文摘要
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.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
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
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
DOI:
10.1186/s40478-023-01508-x
发表时间:
2023-01-12
期刊:
Acta neuropathologica communications
影响因子:
7.1
作者:
[]
通讯作者:
Defining the crucial role of MAGOH in cerebellar development and the potential for targeting the EJC in medulloblastoma treatment
-
批准号:10837315
-
项目类别:
-
资助金额:$34.23万
-
财政年份:2018
-
负责人:Timothy Gershon
-
依托单位:
Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
-
批准号:10462482
-
项目类别:
-
资助金额:$9.54万
-
财政年份:2018
-
负责人:Timothy Gershon
-
依托单位:
Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
-
批准号:9923746
-
项目类别:
-
资助金额:$40.89万
-
财政年份:2018
-
负责人:Timothy Gershon
-
依托单位:
Defining the crucial role of MAGOH in cerebellar development and the potential for targeting the EJC in medulloblastoma treatment
-
批准号:10199065
-
项目类别:
-
资助金额:$33.65万
-
财政年份:2018
-
负责人:Timothy Gershon
-
依托单位:
Glycolytic regulation of cerebellar development and medulloblastoma tumorigenesis
-
批准号:9012118
-
项目类别:
-
资助金额:$32.78万
-
财政年份:2015
-
负责人:Timothy Gershon
-
依托单位:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
-
批准号:8641442
-
项目类别:
-
资助金额:$17.66万
-
财政年份:2012
-
负责人:Timothy Gershon
-
依托单位:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
-
批准号:8433510
-
项目类别:
-
资助金额:$17.66万
-
财政年份:2012
-
负责人:Timothy Gershon
-
依托单位:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
-
批准号:8828814
-
项目类别:
-
资助金额:$17.66万
-
财政年份:2012
-
负责人:Timothy Gershon
-
依托单位:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
-
批准号:8276734
-
项目类别:
-
资助金额:$17.49万
-
财政年份:2012
-
负责人:Timothy Gershon
-
依托单位:
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