Understanding the Mechanisms of TDP-43 Function

了解 TDP-43 功能的机制

基本信息

批准号：
8507420
负责人：
John David Fryer
金额：
$ 19.56万
依托单位：
MAYO CLINIC JACKSONVILLE
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：
2013-02-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507420
关键词：
Amino Acids Amyotrophic Lateral Sclerosis Antibodies Bacterial Artificial Chromosomes Binding Biochemical Biological Biotin C9ORF72 Cell Culture System Cell Nucleus Cells Circular Dichroism Co-Immunoprecipitations Communities DNA DNA Sequence DNA-Binding Proteins Data Disease Embryo Exhibits Frontotemporal Lobar Degenerations Genetic Goals Human Immunochemistry Immunoprecipitation In Vitro Knockout Mice Lead Light Link Mediating Messenger RNA Mus Mutant Strains Mice Mutation N-terminal Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathogenesis Patients Phosphorylation Phosphorylation Site Physiological Progranulin Proteins RNA Recombinants Research Role Sampling Secondary Protein Structure Site Structure Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Tyrosine Tyrosine Phosphorylation Ubiquitin Ubiquitination Urea Western Blotting aspartyl-arginyl-valyl-tyrosyl-isoleucyl-histidyl-prolyl-phenylalanyl-histidyl-leucyl-valyl-isoleucyl-histidine brain cell in vivo in vivo Model insight loss of function mouse model new therapeutic target novel protein TDP-43 public health relevance research study sortilin

项目摘要

DESCRIPTION (provided by applicant): TDP-43 is the principal component of ubiquitin-positive inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Recently, we discovered that TDP-43 is hyper-phosphorylated at tyrosine-4 in disease and pseudo-phosphorylation of tyrosine-4 (TDP- 43Y4D) impairs TDP-43 biological activities. Therefore, our data provide a direct link between TDP-43 phosphorylation and loss of TDP-43 function, which is believed to mediate toxicity and neurodegeneration. We hypothesize that hyper-phosphorylation of TDP-43 at tyrosine-4 contributes to disease pathogenesis by reducing TDP-43 biological activities. Specifically, we will use a combination of in vitro and in vivo models to 1) investigate pathological significance o TDP-43 phosphorylation at tyrosine-4 in disease pathogenesis; 2) investigate the potential mechanisms through which phosphorylation at tyrosine-4 impair TDP-43 biological activities; 3) generate novel bacterial artificial chromosome (BAC) transgenic mouse model expressing human TDP-43Y4D to investigate whether TDP-43Y4D result in loss-of function in vivo. Successful completion of our novel study will undoubtedly enhance the scientific community's understanding of the TDP-43 N-terminus' role, particularly of its N-terminal phosphorylation at tyrosine-4, in disease pathogenesis, might also provide therapeutic approaches. .

描述（由申请人提供）：TDP-43是额颞叶变性伴泛素阳性包涵体（FTLD-TDP）和肌萎缩侧索硬化症（ALS）中泛素阳性包涵体的主要成分。最近，我们发现在疾病中 TDP-43 在 4 号酪氨酸处过度磷酸化，并且 4 号酪氨酸 (TDP-43Y4D) 的假磷酸化会损害 TDP-43 的生物活性。因此，我们的数据提供了 TDP-43 磷酸化和 TDP-43 功能丧失之间的直接联系，TDP-43 功能被认为介导毒性和神经退行性变。我们假设 TDP-43 在酪氨酸 4 处的过度磷酸化通过降低 TDP-43 生物活性来促进疾病发病机制。具体来说，我们将结合使用体外和体内模型来 1) 研究 TDP-43 酪氨酸 4 磷酸化在疾病发病机制中的病理意义； 2) 研究酪氨酸4磷酸化损害TDP-43生物活性的潜在机制； 3) 生成表达人TDP-43Y4D的新型细菌人工染色体（BAC）转基因小鼠模型，以研究TDP-43Y4D是否导致体内功能丧失。我们新研究的成功完成无疑将增强科学界对 TDP-43 N 末端作用的理解，特别是其 N 末端酪氨酸 4 的磷酸化在疾病发病机制中的作用，也可能提供治疗方法。。