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
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: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:
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:
国内基金
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