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Understanding the Mechanisms of Neuropathogenesis

了解神经发病机制

基本信息

批准号：
7825283
负责人：
Michael John Palladino
金额：
$ 28.68万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7825283
关键词：
Affect Alleles Alzheimer&apos s Disease Apoptosis Biochemical Biochemical Pathway Biological Biological Assay Calcium ion Cell Death Cells Dominant-Negative Mutation Drosophila genus Dystonia 12 Familial Hemiplegic Migraine Functional disorder Genes Genetic Genetic Screening Goals Homeostasis Human Impairment In Situ Ischemia Lead Longevity Mediating Membrane Potentials Molecular Molecular Genetics Muscle Mutation Na(+)-K(+)-Exchanging ATPase Necrosis Nerve Degeneration Neurodegenerative Disorders Neurologic Neuronal Dysfunction Neurons Neuropathogenesis Paralysed Pathology Pathway interactions Patients Phenotype Point Mutation Proteins Protocols documentation Pump Research Rest Seizures Site Staining method Stains Structure-Activity Relationship System Techniques Testing Tissues Transgenic Animals Transgenic Organisms Traumatic Brain Injury Ursidae Family age related age related neurodegeneration base genetic analysis in vivo loss of function mutant nervous system disorder neurodegenerative phenotype neuromuscular novel prevent programs progressive neurodegeneration protein B relating to nervous system research study senescence uptake

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the biochemical pathways that regulate age-dependent neuronal viability in metazoans. Using a tractable genetic system to elucidate these pathways and uncover the mechanisms by which they contribute to neurodegenerative diseases and normal senescence, are important goals of my research. We have isolated a number of mutants in an unbiased forward genetic screen that provide us a novel perspective with which to study neuronal senescence and neurodegeneration in vivo. This proposal focuses on mutations that affect ATPalpha (Na/K ATPase), which cause progressive neurodegeneration in Drosophila. In humans loss-of-function Na/K ATPase mutations cause Rapid-onset Dystonia Parkinsonism (RDP) and familial hemiplegic migraines (FHM). Na/K ATPase activity is reduced after ischemia and traumatic brain injury, and is associated with Alzheimer's disease. We hypothesize that neuropathogenesis is mechanistically similar in our mutants and patients with neurological diseases, including RDP and FHM, and propose experiments to elucidate these mechanistic details. Additionally, we propose to identify mutations capable of suppressing the underlying dysfunction and neurodegeneration. We will study these mutants using genetic, molecular, cell biological, and biochemical techniques to elucidate the mechanisms by which the mutations lead to cellular dysfunction and discover how this dysfunction manifests as neurological phenotypes, such as paralysis, seizures and progressive neurodegeneration. Together these specific experiments will elucidate the mechanisms of neuropathogenesis in ATPalpha mutants and lead to a better understanding of age-related neurodegeneration and senescence.

描述（由申请人提供）：本研究计划的长期目标是了解调节后生动物中年龄依赖性神经元活力的生化途径。使用一个易于处理的遗传系统来阐明这些途径，并揭示它们导致神经退行性疾病和正常衰老的机制，是我研究的重要目标。我们已经分离出一些突变体在一个公正的正向遗传筛选，为我们提供了一个新的角度来研究神经元的衰老和神经退行性变在体内。该提案的重点是影响ATPalpha（Na/K ATP酶）的突变，这会导致果蝇进行性神经变性。在人类中，Na/K ATP酶功能丧失突变导致快速发作的肌张力障碍性帕金森综合征（RDP）和家族性偏瘫性偏头痛（FHM）。缺血和脑外伤后，Na/K ATP酶活性降低，与阿尔茨海默病相关。我们假设，神经发病机制是在我们的突变体和神经系统疾病，包括RDP和FHM患者的机制相似，并提出实验来阐明这些机制的细节。此外，我们建议确定能够抑制潜在的功能障碍和神经退行性变的突变。我们将使用遗传、分子、细胞生物学和生物化学技术研究这些突变体，以阐明突变导致细胞功能障碍的机制，并发现这种功能障碍如何表现为神经学表型，如瘫痪、癫痫发作和进行性神经变性。这些具体的实验将阐明ATPalpha突变体的神经发病机制，并导致更好地了解年龄相关的神经退行性变和衰老。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide screen for modifiers of Na (+) /K (+) ATPase alleles identifies critical genetic loci.

DOI：
10.1186/s13041-014-0089-3
发表时间：
2014-12-05
期刊：
Molecular brain
影响因子：
3.6
作者：
Talsma AD;Chaves JF;LaMonaca A;Wieczorek ED;Palladino MJ
通讯作者：
Palladino MJ

Cleavage of mispaired heteroduplex DNA substrates by numerous restriction enzymes.

通过多种限制性酶切割错误配对的异源双链 DNA 底物。

DOI：
发表时间：
2009
期刊：
Current issues in molecular biology
影响因子：
3.1
作者：
Langhans,MarkT;Palladino,MichaelJ
通讯作者：
Palladino,MichaelJ

A novel Drosophila SOD2 mutant demonstrates a role for mitochondrial ROS in neurodevelopment and disease.

DOI：
10.1002/brb3.73
发表时间：
2012-07
期刊：
BRAIN AND BEHAVIOR
影响因子：
3.1
作者：
Celotto, Alicia M.;Liu, Zhaohui;VanDemark, Andrew P.;Palladino, Michael J.
通讯作者：
Palladino, Michael J.

Genetically encoded redox sensor identifies the role of ROS in degenerative and mitochondrial disease pathogenesis.

遗传编码的氧化还原传感器鉴定了ROS在退化性和线粒体疾病发病机理中的作用。

DOI：
10.1016/j.nbd.2011.08.022
发表时间：
2012-01
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Liu, Zhaohui;Celotto, Alicia M.;Romero, Guillermo;Wipf, Peter;Palladino, Michael J.
通讯作者：
Palladino, Michael J.