Bcl-X Dependent Neuropathology

Bcl-X 依赖性神经病理学

基本信息

批准号：
7763814
负责人：
Kevin A Roth
金额：
$ 31.4万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7763814
关键词：
Acute Affect Agonist Anesthetics Apoptosis Apoptotic Attenuated Autophagocytosis BH3 Domain Brain Caspase Cell Culture Techniques Cells Cessation of life Child Complement Data Development Embryo Embryonic Nervous System Ethanol Etiology Event Exhibits Exposure to Family member Fetal Alcohol Syndrome Funding Gene Targeting Genes Genetic Grant Human In Vitro Investigation Link MK801 Mediator of activation protein Mitochondria Modeling Molecular Morphogenesis Mus Mutagens N-Methylaspartate NMDA receptor antagonist Neonatal Nervous system structure Neurons Pathway interactions Pharmaceutical Preparations Physiological Play Population Progress Reports Property Receptor Signaling Relative (related person)Reporting Research Personnel Resistance Role Seizures Series Signal Transduction Spinal Cord Spinal Ganglia Staurosporine Stimulus Structure of trigeminal ganglion TP53 gene Testing Up-Regulation Withdrawal alcohol effect alcohol exposure apoptotic protease-activating factor 1 base caspase-3 caspase-6 caspase-9 in vivo insight mRNA Expression member neonate nervous system development neural precursor cell neuron apoptosis neuron loss neuropathology neurotoxic neurotoxicity neurotrophic factor prevent programs receptor research study response

项目摘要

DESCRIPTION (provided by applicant): In a series of studies supported by this grant, we have demonstrated that the anti-apoptotic Bcl-2 family member Bcl-XL plays a particularly important role in promoting neuron survival. Massive apoptotic death of immature neurons is seen in the Bcl-XL-deficient embryonic nervous system and this effect is prevented by concomitant genetic disruption of bax, apaf-1, caspase-9, or caspase-3. Although the downstream effectors of Bcl-XL and Bax-dependent neuronal death have been largely defined, the critical upstream regulators of this pathway have not. We hypothesize that two members of the pro-apoptotic BH3 domain-only Bcl-2 subfamily, Bim and DPS, act in concert to regulate Bcl-XL:Bax-dependent neuron apoptosis. To critically test this hypothesis, we generated mice carrying various combinations of genetic disruptions in bcl-x, bim, and dp5. Our preliminary studies have demonstrated that both Bim-deficient and DPS-deficient embryos exhibit slightly decreased neuronal programmed cell death and that this effect is markedly enhanced by dual deficiency of Bim and DPS. Interestingly, DPS deficiency significantly reduced immature neuron death throughout the Bcl-XL-deficient embryonic nervous system while Bim deficiency selectively rescued neurons in the trigeminal ganglion. Preliminary studies of telencephalic neurons in vitro suggest that bim and dp5 mRNA expression is regulated by neurotrophic factor signaling. In specific aim one, we will define the neurodevelopmental significance of the Bim/DPS death pathway and characterize the molecular mechanism(s) controlling its activation. In specific aim two, we will determine the in vivo relevance of Bim and DPS in acute ethanol-induced neuron apoptosis in the neonatal mouse brain, a model of human fetal alcohol syndrome, and define the signaling events regulating bim and dp5 expression following ethanol exposure. We have previously shown that acute ethanol neurotoxicity is regulated by the Bcl-XL:Bax- dependent apoptotic pathway and is, at least in part, due to ethanol's NMDA receptor antagonist properties. We now have preliminary in vitro data showing that Bim deficiency inhibits the neuronal death inducing action of MK801, a potent NMDA receptor antagonist. In total, these studies will yield new insights into the molecular pathways regulating both physiological and pathological neuron death.

描述（由申请人提供）：在本次资助支持的一系列研究中，我们证明了抗凋亡 Bcl-2 家族成员 Bcl-XL 在促进神经元存活方面发挥着特别重要的作用。在 Bcl-XL 缺陷的胚胎神经系统中观察到未成熟神经元的大量凋亡，这种效应可以通过同时破坏 bax、apaf-1、caspase-9 或 caspase-3 来阻止。尽管 Bcl-XL 和 Bax 依赖性神经元死亡的下游效应器已基本确定，但该通路的关键上游调节器尚未确定。我们假设仅促凋亡 BH3 结构域的 Bcl-2 亚家族的两个成员 Bim 和 DPS 协同作用，调节 Bcl-XL:Bax 依赖性神经元凋亡。为了严格检验这一假设，我们培育了携带 bcl-x、bim 和 dp5 基因破坏的各种组合的小鼠。我们的初步研究表明，Bim 缺陷和 DPS 缺陷胚胎均表现出神经元程序性细胞死亡略有减少，并且 Bim 和 DPS 双重缺陷显着增强了这种效应。有趣的是，DPS 缺陷显着减少了整个 Bcl-XL 缺陷胚胎神经系统中未成熟神经元的死亡，而 Bim 缺陷则选择性地挽救了三叉神经节中的神经元。体外端脑神经元的初步研究表明，bim 和 dp5 mRNA 表达受神经营养因子信号传导调节。在具体目标一中，我们将定义 Bim/DPS 死亡途径的神经发育意义，并描述控制其激活的分子机制。在具体目标二中，我们将确定 Bim 和 DPS 在新生小鼠大脑（人类胎儿酒精综合征模型）中急性乙醇诱导的神经元凋亡中的体内相关性，并定义乙醇暴露后调节 bim 和 dp5 表达的信号事件。我们之前已经表明，急性乙醇神经毒性是由 Bcl-XL:Bax 依赖性细胞凋亡途径调节的，并且至少部分是由于乙醇的 NMDA 受体拮抗剂特性。我们现在有初步的体外数据表明，Bim 缺乏会抑制 MK801（一种有效的 NMDA 受体拮抗剂）的神经元死亡诱导作用。总的来说，这些研究将对调节生理和病理神经元死亡的分子途径产生新的见解。

项目成果

期刊论文数量（45）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immunohistochemical detection with quantum dots.

DOI：
10.1385/1-59745-369-2:11
发表时间：
2007
期刊：
Methods in molecular biology
影响因子：
0
作者：
Rizwan S. Akhtar;C. B. Latham;D. Siniscalco;Carlo Fuccio;K. Roth
通讯作者：
Rizwan S. Akhtar;C. B. Latham;D. Siniscalco;Carlo Fuccio;K. Roth

Autophagy in brain tumors: a new target for therapeutic intervention.

DOI：
10.1111/j.1750-3639.2011.00544.x
发表时间：
2012-01
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
0
作者：
Kaza N;Kohli L;Roth KA
通讯作者：
Roth KA

bcl-2/Adenovirus E1B 19-kd interacting protein 3 (BNIP3) regulates hypoxia-induced neural precursor cell death.

DOI：
10.1097/nen.0b013e3181c3b9be
发表时间：
2009-12
期刊：
Journal of neuropathology and experimental neurology
影响因子：
3.2
作者：
Walls KC;Ghosh AP;Ballestas ME;Klocke BJ;Roth KA
通讯作者：
Roth KA

Altered regulation of phosphatidylinositol 3-kinase signaling in cathepsin D-deficient brain.

组织蛋白酶 D 缺陷大脑中磷脂酰肌醇 3-激酶信号传导的调节发生改变。

DOI：
10.4161/auto.3822
发表时间：
2007
期刊：
Autophagy
影响因子：
13.3
作者：
Walls,KenC;Klocke,BarbaraJ;Saftig,Paul;Shibata,Masahiro;Uchiyama,Yasuo;Roth,KevinA;Shacka,JohnJ
通讯作者：
Shacka,JohnJ

The proapoptotic BH3-only, Bcl-2 family member, Puma is critical for acute ethanol-induced neuronal apoptosis.