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Investigation of modifiers of TDP-43 neurotoxicity in ALS models

ALS 模型中 TDP-43 神经毒性调节剂的研究

基本信息

批准号：
8966664
负责人：
Nicole Faron Liachko
金额：
--
依托单位：
VA PUGET SOUND HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8966664
关键词：
Affect American Americas Amyotrophic Lateral Sclerosis Behavior Behavioral Biochemistry Brain CDC7 gene Caenorhabditis elegans Cell Culture Techniques Cell model Cessation of life Characteristics Complementary DNA Complex DNA Damage Dementia Detergents Development Diagnosis Disease Drug Kinetics Elderly Exhibits Frontotemporal Lobar Degenerations Gene Expression Gene Targeting Genes Genetic Genetic Techniques Human Institutes Intervention Investigation Lead Libraries Life Mammalian Cell Medicine Military Personnel Modeling Molecular Molecular Biology Motor Mus Muscular Atrophy Mutate Mutation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuroglia Neurologic Neurons Organism Paralysed Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Post-Translational Protein Processing Proteins Regulator Genes Risk Services Spinal Cord Surveys Temporal Lobe Testing Therapeutic Therapeutic Intervention Transgenic Mice Transgenic Organisms Translating United States National Academy of Sciences Veterans Whole Organism Work base cognitive change design disability frontal lobe in vivo inhibitor/antagonist insight motor neuron degeneration neuron loss neurotoxicity new therapeutic target novel premature prevent protein TDP-43 protein aggregate public health relevance research study response small molecule small molecule inhibitor small molecule libraries targeted treatment therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease characterized by degeneration of motor neurons in the brain and spinal cord, resulting in neurogenic muscle wasting, paralysis, and death. Nearly 95% of ALS cases have pathology featuring ubiquitinated and hyperphosphorylated inclusions of the TDP-43 protein in neurons and glial cells. Similar inclusions of TDP-43 are hallmarks of another neurodegenerative disease, frontotemporal lobar degeneration (FTLD-TDP), which is a major cause of mid- to late-life dementia. An understanding of the mechanisms controlling TDP-43 pathology in ALS and FTLD-TDP is critical to the design of neuroprotective strategies. TDP-43 is directly phosphorylated by the kinase CDC7, and this phosphorylation drives TDP-43 neurotoxicity and resultant neurodegeneration. This proposal describes experiments exploring the cellular and molecular changes that promote TDP-43 targeted CDC7 kinase activity, with a focus on the development of therapeutic interventions for the treatment of TDP-43 proteinopathies such as ALS and FTLD-TDP. Disease specific changes in CDC7 may promote TDP-43 phosphorylation. In fact, increased CDC7 protein levels and post-translational modifications of CDC7 are observed in parallel with pathological TDP-43 phosphorylation in a mammalian cell model of TDP-43 phosphorylation. CDC7 protein levels, localization, post-translational modifications, and gene expression will be evaluated in mouse primary neuron culture, mammalian cell culture, and transgenic C. elegans models exhibiting TDP-43 phosphorylation using molecular biology, biochemistry, and genetics techniques. Characterizing disease-relevant changes in CDC7 will further our understanding of the causes of TDP-43 pathology in ALS and FTLD-TDP. To identify pathway(s) controlling CDC7 kinase activation in neurons, CDC7 kinase regulators, pathway genes, and co-factors have been surveyed for effects on TDP-43 phosphorylation. The DNA damage response (DDR) pathway was identified by this screen as a key regulator of TDP-43 phosphorylation. Components of the DDR pathway will be evaluated in detail using mouse primary neurons, C. elegans and mammalian cell models of TDP-43 proteinopathy. The determination of the genes and gene pathways regulating TDP-43 targeted CDC7 kinase activity will provide insight into disease pathobiology, and potentially identify novel therapeutic targets for intervention. CDC7 is a promising therapeutic target for th inhibition of pathological TDP-43 phosphorylation that is observed in ALS and FTLD-TDP. However, small molecule inhibitors specific for CDC7 with appropriate pharmacokinetics in vivo are not commercially available. Therefore, a targeted library of small molecules structurally similar to CDC7 inhibitors will be assembled. These small molecules will be surveyed for specific inhibition of CDC7 kinase activity, and tested in vivo in C. elegans and in mammalian cell culture models for protection against TDP-43 driven neurodegeneration. This is a critical step towards developing viable treatments for ALS and FTLD-TDP.

描述（由申请人提供）：