IS THERE A ROLE FOR ENDOPLASMIC RETICULUM STRESS IN THE PATHOGENESIS OF ALS?
内质网应激在 ALS 的发病机制中是否发挥作用?
基本信息
- 批准号:nhmrc : 454749
- 负责人:
- 金额:$ 35.72万
- 依托单位:
- 依托单位国家:澳大利亚
- 项目类别:NHMRC Project Grants
- 财政年份:2007
- 资助国家:澳大利亚
- 起止时间:2007-01-01 至 2009-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Motor neuron disease (MND) is a devastating and rapidly progressing adult onset disease; most patients die 2-5 years after diagnosis. MND is characterized by the death of specific cells, called 'motor neurons' within the nervous system. Unfortunatley, MND currently has an unknown cause and no effective treatment. This proposal aims to study the mechanisms that trigger degeneration of motor neurons in MND. Some forms of MND are inherited and linked to mutations in a protein called SOD1, but how the mutations lead to cell death is unclear. However, SOD1 mutants are known to clump together in large aggregates and this is linked to toxicity. In a previous study, we found that normally SOD1 is secreted from the cell where it can protect the motor neuron from oxidative damage. However SOD1 mutants are not secreted as well as the normal protein, leaving the cell vulnerable to damage. In addition, the compartment of the cell responsible for secretion,the 'endoplasmic reticulum' (ER), is under stress due to secretory dysfunction of mutant SOD1. Our data suggest that this ER stress leads to the activation of 'cell suicide' pathways, leading to death of the motor neuron. However, very little is known about how molecular events in the ER lead to cell death in MND. This proposal will examine these processes in detail. In other studies, we found that a molecule called 'PDI' inhibits mutant SOD1 from aggregation and is made in large quantities in our laboratory models of MND. This proposal will determine if PDI is potentially a new therapeutic target for MND due its ability to protect the cell from the toxic effects of SOD1 aggregation. Our findings are both novel and exciting and propose previously unexplored mechanisms of disease and new theraputic targets. Once we understand the basic mechanisms occuring in the motor neuron, which we can design specific therapies to halt the progression of the disease and prolong the life of human MND patients.
运动神经元病(MND)是一种破坏性强且进展迅速的成人发病疾病;大多数患者在诊断后2-5年死亡。MND的特点是神经系统中被称为“运动神经元”的特定细胞死亡。不幸的是,MND目前病因不明,也没有有效的治疗方法。本研究旨在探讨MND运动神经元退化的机制。一些形式的MND是遗传的,与一种叫做SOD1的蛋白质的突变有关,但突变是如何导致细胞死亡的尚不清楚。然而,已知SOD1突变体会大量聚集在一起,这与毒性有关。在之前的研究中,我们发现正常情况下,SOD1是由细胞分泌的,它可以保护运动神经元免受氧化损伤。然而,SOD1突变体不像正常蛋白那样分泌,使细胞容易受到损伤。此外,由于SOD1突变体的分泌功能障碍,负责分泌的细胞室内质网(ER)也处于应激状态。我们的数据表明,内质网应激导致“细胞自杀”途径的激活,导致运动神经元的死亡。然而,对于内质网中的分子事件如何导致MND中的细胞死亡,我们知之甚少。本建议将详细研究这些过程。在其他研究中,我们发现一种名为“PDI”的分子抑制突变SOD1的聚集,并且在我们的MND实验室模型中大量产生。由于PDI能够保护细胞免受SOD1聚集的毒性作用,这一提议将确定PDI是否可能成为MND的新治疗靶点。我们的发现既新颖又令人兴奋,并提出了以前未被探索的疾病机制和新的治疗靶点。一旦我们了解了运动神经元发生的基本机制,我们就可以设计出特定的治疗方法来阻止疾病的发展,延长人类精神病患者的生命。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
A/Pr Julie Atkin其他文献
A/Pr Julie Atkin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('A/Pr Julie Atkin', 18)}}的其他基金
Validating the NLRP3 Inflammasome as a Therapeutic Target in Motor Neuron Disease
验证 NLRP3 炎症小体作为运动神经元疾病的治疗靶点
- 批准号:
nhmrc : 1145820 - 财政年份:2018
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
Validating the NLRP3 Inflammasome as a Therapeutic Target in Motor Neuron Disease
验证 NLRP3 炎症小体作为运动神经元疾病的治疗靶点
- 批准号:
nhmrc : GNT1145820 - 财政年份:2018
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis
深入了解家族性和散发性额颞叶痴呆和肌萎缩侧索硬化症的分子起源
- 批准号:
nhmrc : GNT1095215 - 财政年份:2016
- 资助金额:
$ 35.72万 - 项目类别:
Boosting Dementia Research Initiative
The role of mutant cyclin F in amyotrophic lateral sclerosis
突变细胞周期蛋白F在肌萎缩侧索硬化症中的作用
- 批准号:
nhmrc : GNT1107644 - 财政年份:2016
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
Disruption to intracellular trafficking as a central pathogenic mechanism in amyotrophic lateral sclerosis (ALS)
细胞内运输中断是肌萎缩侧索硬化症 (ALS) 的主要致病机制
- 批准号:
nhmrc : 1086887 - 财政年份:2015
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
Disruption to intracellular trafficking as a central pathogenic mechanism in amyotrophic lateral sclerosis (ALS)
细胞内运输中断是肌萎缩侧索硬化症 (ALS) 的主要致病机制
- 批准号:
nhmrc : GNT1086887 - 财政年份:2015
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
A central role for ER-Golgi trafficking in motor neuron disease
ER-高尔基体运输在运动神经元疾病中的核心作用
- 批准号:
nhmrc : 1030513 - 财政年份:2012
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
Protein Disulphide Isomerase and Neurodegeneration in Motor Neuron Disease
蛋白质二硫化物异构酶和运动神经元疾病中的神经变性
- 批准号:
nhmrc : 1006141 - 财政年份:2011
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
Protein Disulphide Isomerase and Motor Neuron Disease
蛋白质二硫键异构酶与运动神经元疾病
- 批准号:
nhmrc : GNT1006141 - 财政年份:2011
- 资助金额:
$ 35.72万 - 项目类别:
Project Grants
相似海外基金
Role of RNF213 as a novel endoplasmic reticulum stress regulator in diabetes mellitus.
RNF213 作为新型内质网应激调节剂在糖尿病中的作用。
- 批准号:
22K10487 - 财政年份:2022
- 资助金额:
$ 35.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of endoplasmic reticulum calcium in beta cell mitochondrial dysfunction, senescence, and onset of type 1 diabetes
内质网钙在 β 细胞线粒体功能障碍、衰老和 1 型糖尿病发病中的作用
- 批准号:
10537643 - 财政年份:2022
- 资助金额:
$ 35.72万 - 项目类别:
The role of NADPH production in regulating endoplasmic reticulum function and the progression of non-alcoholic steatohepatitis
NADPH产生在调节内质网功能和非酒精性脂肪性肝炎进展中的作用
- 批准号:
10386489 - 财政年份:2022
- 资助金额:
$ 35.72万 - 项目类别:
Uncovering the Role of UFM1 in the Release of Arrested Peptides from Stalled Ribosomes at the Endoplasmic Reticulum (ER) Membrane
揭示 UFM1 在内质网 (ER) 膜上停滞核糖体释放停滞肽中的作用
- 批准号:
10462233 - 财政年份:2022
- 资助金额:
$ 35.72万 - 项目类别:
Role of altered endoplasmic reticulum calcium regulation and the N-methyl-D-aspartate (NMDA) receptor signaling in cortico-striatal synaptic dysfunction: Opportunities for therapy in prodromal Huntington disease
改变的内质网钙调节和 N-甲基-D-天冬氨酸 (NMDA) 受体信号在皮质纹状体突触功能障碍中的作用:前驱期亨廷顿病的治疗机会
- 批准号:
443591 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Operating Grants
Novel role of endoplasmic reticulum-associated degradation in iron metabolism
内质网相关降解在铁代谢中的新作用
- 批准号:
10364117 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Investigating the role of Reep5 in formation, maintenance, and function of the endoplasmic reticulum
研究 Reep5 在内质网形成、维持和功能中的作用
- 批准号:
RGPIN-2016-05618 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Discovery Grants Program - Individual
RUI: Role of the Endoplasmic Reticulum in mediating cell fate
RUI:内质网在介导细胞命运中的作用
- 批准号:
2127729 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Continuing Grant
The role of endoplasmic reticulum-mitochondria contacts in neurodegeneration
内质网-线粒体接触在神经退行性变中的作用
- 批准号:
2607107 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Studentship
Novel role of endoplasmic reticulum-associated degradation in iron metabolism
内质网相关降解在铁代谢中的新作用
- 批准号:
10532368 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别: