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AMPA/Kainate Receptors, Free Radicals, And Motor Neuron Injury

AMPA/红藻氨酸受体、自由基和运动神经元损伤

基本信息

批准号：
7742985
负责人：
JOHN H WEISS
金额：
$ 32.98万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-06-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7742985
关键词：
Accounting Acute Age Animal Disease Models Animal Model Animals Astrocytes Cells Characteristics Clinical Development Disease Disease Pathway Disease model Event Evolution Free Radicals Functional disorder Generations Glutamate Receptor Glutamate Transporter Glutamates Horns Inflammatory Infusion procedures Inherited Injury Intervention Kainic Acid Receptors Lead Light Link Mediating Mitochondria Modeling Monitor Motor Neurons Mus Mutant Strains Mice Mutation Neurons Oxidative Stress Pathogenesis Pathologic Processes Pathology Pattern Peroxonitrite Pharmaceutical Preparations Process Reactive Oxygen Species Research Personnel Site Slice Source Spinal Cord Suggestion Superoxide Dismutase Testing Therapeutic Tissues Transgenic Model Uncertainty Wild Type Mouse base design disease phenotype extracellular feeding in vivo in vivo Model motor neuron injury mutant neuron loss novel oxidation oxidative damage programs response treatment strategy uptake

项目摘要

Observations of increased CSF glutamate in ALS, together with findings that motor neurons (MNs) are selectively vulnerable to glutamate receptor mediated ("excitotoxic") injury support an excitotoxic contribution to MN loss in the disease. Past studies have highlighted factors that may underlie this vulnerability; in comparison to most other neurons, excitotoxic activation of MNs induces greater mitochondrial Ca2+ overload and exceptionally strong reactive oxygen species (ROS) generation. However, while astroglial glutamate transporters account for most glutamate uptake in the CMS,and their damage appears to underlie extracellular glutamate elevations in ALS, the reason for their dysfunction has been unclear. Providing a possible clue, recent studies suggest that this ROS generated within MNs in response to excitotoxic activation may in itself cause disruption of glutamate uptake in surrounding astrocytes. These observations suggest a mechanism that causatively links excitotoxic MN damage with oxidative disruption of glutamate transport, and provide the basis the for a feed forward model of ALS, in which a range of inciting factors could lead into a common disease pathway. The broad aim of this proposal is to use culture and slice models to extend these studies and further examine the hypothesis that ROS generation within MNs contributes to the loss of regional glutamate transport in vivo. Excitotoxic ROS generation within MNs and its ability to penetrate surrounding tissue and disrupt glutamate transport will be examined in dissociated and slice culture models from wild type mice as well as mice harboring superoxide dismutase (SOD) mutations associated with familial forms of ALS (which provide the best animal models of the disease). SOD mutant mice will be used to examine the degree to which oxidative changes and disruption of transport occurs in regions immediately surrounding large ventral horn MNs, as would be predicted if the MNs are the source of the ROS. Finally, the ability of selected pharmacological interventions to decrease these pathological processes will be tested in slice and animal models. It is hoped that these studies will further clarify sequences of events culminating in selective MN loss in ALS, and thereby facilitate development of new treatment strategies.

ALS患者脑脊液谷氨酸升高的观察，以及运动神经元（MNs）的变化

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice.

DOI：
10.1038/cddis.2012.115
发表时间：
2012-08-16
期刊：
Cell death & disease
影响因子：
9
作者：
通讯作者：

The homozygote VCP(R¹⁵⁵H/R¹⁵⁵H) mouse model exhibits accelerated human VCP-associated disease pathology.

DOI：
10.1371/journal.pone.0046308
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Nalbandian A;Llewellyn KJ;Kitazawa M;Yin HZ;Badadani M;Khanlou N;Edwards R;Nguyen C;Mukherjee J;Mozaffar T;Watts G;Weiss J;Kimonis VE
通讯作者：
Kimonis VE

Marked synergism between mutant SOD1 and glutamate transport inhibition in the induction of motor neuronal degeneration in spinal cord slice cultures.

DOI：
10.1016/j.brainres.2012.02.005
发表时间：
2012-04-11
期刊：
Brain research
影响因子：
2.9
作者：
Yin HZ;Weiss JH
通讯作者：
Weiss JH

A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse.

DOI：
10.1002/mus.23522
发表时间：
2013-02
期刊：
MUSCLE & NERVE
影响因子：
3.4
作者：
Nalbandian, Angele;Llewellyn, Katrina J.;Badadani, Mallikarjun;Yin, Hong Z.;Nguyen, Christopher;Katheria, Veeral;Watts, Giles;Mukherjee, Jogeshwar;Vesa, Jouni;Caiozzo, Vincent;Mozaffar, Tahseen;Weiss, John H.;Kimonis, Virginia E.
通讯作者：
Kimonis, Virginia E.

Ca permeable AMPA channels in diseases of the nervous system.