Molecular Mechanism of Spinal Cord Neurodegeneration

脊髓神经变性的分子机制

基本信息

批准号：
7585654
负责人：
Michael P Kurnellas
金额：
$ 1.92万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-02 至 2009-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7585654
关键词：
Acetylcholine Acute Afferent Neurons Agreement Animal Model Antibodies Apoptosis Apoptotic Astrocytes Attention Biological Assay C-terminal Calcitonin Calcium Calpain Caspase Cell Death Cells Cessation of life Chronic Complement Receptor Confocal Microscopy Cytoskeletal Proteins Disease Equilibrium Exhibits Experimental Autoimmune Encephalomyelitis Fellowship Functional disorder Genes Glial Fibrillary Acidic Protein Goals Hindlimb Homeostasis ITGAM gene In Vitro Individual Induction of Apoptosis Inflammatory Injury Investigation Ions Knockout Mice Label Lead Lumbar spinal cord structure Macrophage-1 Antigen Measures Mediating Microglia Molecular Motor Neurons Multiple Sclerosis Names Nerve Degeneration Neurodegenerative Disorders Neurofilament-H Neurologic Neuronal Injury Neurons Oligodendroglia Optics PMCA1 protein Pathology Peptide Hydrolases Peptides Phosphoric Monoester Hydrolases Play Poly(ADP-ribose) Polymerases Protein Dephosphorylation Protein Isoforms Protein phosphatase Proteins Pump Role Small Interfering RNA Spectrin Spinal Cord Substance P Swelling Symptoms Testing Time Western Blotting Wild Type Mouse base calpain inhibitor calpastatin caspase-3 esterase immunocytochemistry immunoreactivity in vitro activity in vivo inhibitor/antagonist mitochondrial dysfunction motor deficit neurofilament neuron loss peripherin postnatal prevent research study

项目摘要

DESCRIPTION (provided by applicant): The molecular mechanisms underlying neuronal and axonal pathology in neurodegenerative and inflammatory diseases including multiple sclerosis remain unclear. However, increasing evidence indicates that ion dyshomeostasis, particularly disruption of calcium balance, may play a pivotal role in neuronal and axonal injury. The purpose of these studies is to examine how the deficiency in plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump involved in neuronal calcium extrusion, leads to dysfunction and death of spinal cord neurons. It is hypothesized that the lack of PMCA2 causes neuronal injury due to induction of calpain, a calcium-activated protease which, in turn, degrades cytoskeletal proteins and especially non-phosphoryated neurofilaments. Furthermore, it is proposed that PMCA2 deficiency leads to mitochondrial dysfunction and apoptosis. This hypothesis is investigated by use of a PMCA inhibitor in pure spinal cord neuronal cultures as well as PMCA2-null mice, which exhibit motor deficits due to loss of spinal cord motor neurons.

描述（由申请人提供）：神经退行性疾病和炎症性疾病（包括多发性硬化症）的神经元和轴突病理的分子机制尚不清楚。但是，越来越多的证据表明，尤其是钙平衡破坏的离子异势症可能在神经元和轴突损伤中起关键作用。这些研究的目的是检查质膜ATPase同工型2（PMCA2）的缺乏，这是一种参与神经钙挤出的主要泵，导致脊髓神经元的功能障碍和死亡。假设缺乏PMCA2会导致钙蛋白酶诱导，这是一种钙激活的蛋白酶，从而降解细胞骨架蛋白，尤其是非磷酸化的神经丝。此外，建议PMCA2缺乏会导致线粒体功能障碍和凋亡。通过在纯脊髓神经元培养物中使用PMCA抑制剂以及PMCA2-NULL小鼠来研究该假设，这些小鼠由于脊髓运动神经元的丧失而表现出运动不足。