Regulation mechanism and functional genomics of LINE1 RNA in TDP-43 linked neurodegeneration

TDP-43相关神经变性中LINE1 RNA的调控机制和功能基因组学

基本信息

批准号：
10518877
负责人：
Xianjun Dong
金额：
$ 87.74万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518877
关键词：
ALS patients Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Autopsy C9ORF72 Chromatin Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Damage Data Degradation Pathway Development Disease Elements Euchromatin Event Family Feedback Frontotemporal Dementia Functional disorder Gene Expression Genes Genetic Genetic Transcription Genome Genomic approach Genomics Goals Human Human Genome Length Link Mediating Messenger RNA Mobile Genetic Elements Modification Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathologic Pathology Pathway interactions Patients Play Point Mutation Process RNA RNA Decay RNA Degradation RNA Processing RNA Splicing RNA metabolism RNA-Binding Proteins Regulation Relaxation Reporting Research Project Grants Retroelements Retrotransposition Retrotransposon Reverse Transcriptase Inhibitors Role Site Techniques Tissues Transcript Transcriptional Activation Untranslated RNA Up-Regulation embryonic stem cell functional genomics gene network genome-wide genomic locus histone modification improved induced pluripotent stem cell interest knock-down loss of function protein TDP-43 stem cell differentiation therapy development

项目摘要

Dysfunction of RNA metabolism has emerged to play crucial roles in multiple neurodegeneration diseases, including Alzheimer’s Disease (AD) and Alzheimer’s Disease related dementias (ADRD), such as frontal temporal dementia (FTD). One pathologic hallmark of these diseases is the nuclear clearance and cytosolic aggregation of the RNA binding protein (RBP) TAR DNA binding protein-43 (TDP-43), which is found in 20-60% AD patients and 50% FTD patients. TDP-43 has multiple functions in mRNA processing. It is also implicated in regulating retrotransposon activation, but the molecular mechanism is not resolved. Retrotransposon elements are mobile genetic elements that copy themselves by transcribing into RNA, reverse-transcribed into DNA and then inserted into new sites in the genome, a process known as retrotransposition. Long interspersed nuclear element-1 (LINE1) is the only currently active, autonomous family of retrotransposon elements in human, and accounts for ~20% of the human genome. Only a small subset of LINE1s are thought to be mobile. The majority are inactive due to truncations, rearrangements and point mutations. There are increasing interest in understanding the “noncoding RNA” functions of LINE1 RNA in chromatin state regulation. In this research project, we will decipher the molecular mechanism of LINE1 RNA dysregulation, particularly the dysfunction of LINE1 RNA decay pathway caused by TDP-43 loss of function, which is associated with the pathology of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. We will determine the causal relationship of LINE1 RNA elevation with chromatin accessibility, histone modification and transcriptional gene network disruption. We will combine human induced pluripotent stem cell-differentiated neurons and postmortem tissues from AD and FTD patients to dissect the molecular mechanisms associated with TDP-43 proteiopathy. Our proposed study will provide deeper mechanistic understanding of the retroelement dysregulation in AD/ADRD and its role in functional genomics, which is largely understudied in the past. The findings will help understanding disease mechanisms and facilitating therapy development for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias.

RNA代谢功能障碍已出现在包括阿尔茨海默氏病（AD）和阿尔茨海默氏病有关的多种神经变性疾病中起关键作用，例如额叶临时痴呆症（FTD）。这些疾病的一个病理标志是RNA结合蛋白（RBP）TAR DNA结合蛋白-43（TDP-43）的核清除和胞质聚集，这在20-60％的AD AD患者和50％的FTD患者中发现。 TDP-43在mRNA处理中具有多个功能。它也与控制返回跨座子激活有关，但分子机制尚未解决。逆转录元素元素是移动遗传元件，通过转录RNA，反转录到DNA中，然后插入基因组中的新位点，该过程被称为逆转录词。长期散布的核元素-1（LINE1）是人类中唯一活跃的逆转录元元素的自主家族，占人类基因组的约20％。只有一小部分LINE1被认为是移动的。由于截断，重排和点突变，大多数是无效的。在理解染色质状态调节中LINE1 RNA的“非编码RNA”功能的兴趣越来越大。在该研究项目中，我们将解释LINE1 RNA失调的分子机制，特别是TDP-43功能丧失引起的Line1 RNA衰变途径的功能障碍，这与阿尔茨海默氏病和阿尔茨海默氏病有关的病理学有关。我们将确定Line1 RNA升高与染色质可及性，组蛋白修饰和转录基因网络破坏的因果关系。我们将结合人类诱导的多能干细胞分化的神经元和来自AD和FTD患者的死后组织，以剖析与TDP-43蛋白质病有关的分子机制。我们提出的研究将对AD/ADRD的追溯失调及其在功能基因组中的作用提供更深入的机械理解，这在过去很大程度上被理解了。这些发现将有助于了解阿尔茨海默氏病和阿尔茨海默氏病与痴呆症相关的疾病机制并促进治疗发展。