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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

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.