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：
10697326
负责人：
Xianjun Dong
金额：
$ 83.4万
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/10697326
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 Neuronal Differentiation 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 Reverse Transcription Role Site Techniques Tissues Transcript Transcriptional Activation Untranslated RNA Up-Regulation embryonic stem cell functional genomics gene network genetic element genome-wide genomic locus histone modification improved induced pluripotent stem cell interest knock-down loss of function neuronal survival 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 代谢功能障碍在多种神经退行性疾病中发挥着至关重要的作用，包括阿尔茨海默病 (AD) 和阿尔茨海默病相关痴呆 (ADRD)，例如额颞叶痴呆 (FTD)，这些疾病的病理特征之一是核清除和核清除。 RNA 结合蛋白 (RBP) TAR DNA 结合蛋白-43 (TDP-43) 的胞质聚集，存在于 20-60% AD 患者和 50% FTD 患者中TDP-43 在 mRNA 加工中具有多种功能，也参与调节逆转录转座子的激活，但其分子机制尚未解决。逆转录转座子元件是可移动的遗传元件，它们通过转录成RNA、逆转录成DNA然后插入到基因组中的新位点来复制自身，这一过程被称为长散布元件核-1 (LINE1)，是目前唯一活跃的、人类逆转录转座子元件的自主家族，占人类基因组的约 20%，认为 LINE1 中的大多数是可移动的。人们越来越有兴趣了解 LINE1 RNA 在染色质状态调节中的“非编码 RNA”功能。在这个研究项目中，我们将破译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，这与阿尔茨海默病和阿尔茨海默病相关痴呆的病理学有关。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多能干细胞分化的神经元和来自 AD 和死后的组织。 FTD 患者剖析与 TDP-43 蛋白病相关的分子机制，我们提出的研究将为 AD/ADRD 中的逆转录元件失调及其在功能基因组学中的作用提供更深入的机制理解，这些发现将有助于理解。疾病机制并促进阿尔茨海默病和阿尔茨海默病相关痴呆症的治疗开发。