| Project/Area Number |
22500322
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Meiji Pharmaceutical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
天竺桂 弘子 明治薬科大学, 薬学部, 助教 (80434190)
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| Co-Investigator(Renkei-kenkyūsha) |
有馬 邦正 明治薬科大学, 薬学部, 助教 (20250227)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | TDP-43 / 標的遺伝子 / 結合タンパク質 / 分子ネットワーク / 筋萎縮性側索硬化症 / 神経細胞死 / 次世代シークエンサー / バイオインフォマティクス / インターラクトーム / ブロテオミクス / ブロテインアレイ |
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| Research Abstract |
TAR DNA-binding protein-43 (TDP-43) is an evolutionarily conservednuclear protein that regulates gene expression by forming a multimolecular complex with a wide varietyof target RNAs and interacting proteins. Abnormally phosphorylated, ubiquitinated, and aggregatedTDP-43 proteins constitute a principal component of neuronal and glial cytoplasmic and nuclearinclusions in the brains of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), establishing a novel clinical entity designated TDP-43 proteinopathy. Althoughincreasing evidence suggests that the neurodegenerative process underlying ALS and FTLD isattributable to a toxic gain of function or a loss of cellular function of TDP-43, the precise molecularmechanisms remain largely unknown. Recent advances in systems biology enable us to characterize theglobal molecular network extracted from large-scale data of the genome, transcriptome, and proteomewith the pathway analysis tools of bioiformatics endowed with a comprehensive knowledge base. Thepresent study was conducted to characterize the comprehensive molecular network of TDP-43 targetRNAs and interacting proteins, recently identified by deep sequencing with next-generation sequencersand mass spectrometric analysis. Our results propose the systems biological view that TDP-43 serves as a molecular coordinator of the RNA-dependent regulation of gene transcription and translation pivotal for performing diverse neuronal functions and that the disruption of TDP-43-mediated molecularcoordination induces neurodegeneration in ALS and FTLD.
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