Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains

阿尔茨海默病大脑中逆转录酶依赖性基因多样化机制的改变

基本信息

批准号：
10758986
负责人：
JEROLD CHUN
金额：
$ 8.38万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10758986
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid beta-Protein Precursor Animal Experiments Animal Model Autopsy Back Biological Models Brain Brain region Cell model Complementary DNA Copy Number Polymorphism DNA DNA strand break Data Disease Down Syndrome FDA approved Female Foundations Gene Proteins Genes Genetic Recombination Genetic Transcription Genome Genomics HIV Human IACUC In Situ Hybridization Institutional Review Boards Knowledge Methodology Modeling Molecular Molecular Biology Molecular Neurobiology Molecular Target Mosaicism Nature Neurofibrillary Tangles Neuroglia Neurons Nucleotides Pathogenicity Patients Pattern Prevalence Publishing RNA RNA-Directed DNA Polymerase Reporting Reverse Transcriptase Inhibitors Role Sampling Senile Plaques Testing Therapeutic Toxic effect Validation Variant aged brain tissue cell type ds-DNA familial Alzheimer disease genetic variant human embryonic stem cell induced pluripotent stem cell integration site male mosaic nanobodies neurobiological mechanism neuropathology new therapeutic target novel sequencing platform sex therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT We have identified somatic gene recombination (SGR) in neurons of the human brain, with particular relevance to sporadic Alzheimer’s disease (SAD) (Nature 563, 639-645 (2018)). This discovery represents a new and functionally significant aspect of genomic mosaicism (eLife;4:e05116 (2015)) that has genuine therapeutic potential through newly identified molecular targets. Indeed, we found that SGR, acting on the AD gene for Amyloid Precursor Protein (APP), produces thousands of distinct forms of APP, some of which are enriched in or unique to AD. The APP gene variations related to AD that were analyzed thus far include copy number variations (CNVs) and at least 11 single-nucleotide variations (SNVs) that were previously reported as pathogenic in familial AD, yet that arose somatically and mosaically in SAD; these variations were absent from non-diseased neurons. SGR utilizes reverse transcriptase (RT) activity on transcribed RNAs that, combined with DNA strand-breaks and APP gene transcription, produce double-stranded DNA that is retro-inserted back into the genome to form “genomic cDNAs” (gencDNAs). These published data contribute to the scientific foundation on which the current proposal will build, to test the hypothesis that altered SGR, involving brain-specific reverse transcriptases, functionally contributes to AD and affects multiple genes, providing novel targets for AD therapies. Postmortem IRB-approved and de-identified brain samples from validated AD donors of both sexes will be compared to non-diseased controls, while IACUC-approved animal experiments will model SGR and its AD-relevant endpoints. Three Aims will be pursued over 5 years. Aim 1 will define the molecular neurobiology of APP gencDNA diversity and identify new SGR genes enhanced in AD brains. Aim 2 will determine expression and function of SGR genes in AD brain and model systems. Aim 3 will identify genes responsible for RT SGR activity within normal and AD brains. This proposal will thus open new vistas into AD via novel SGR mechanisms and will identify new therapeutic targets for the treatment of AD.

项目摘要/摘要我们已经确定了人脑神经元中的体细胞基因重组（SGR），与零星的阿尔茨海默氏病（SAD）特别相关（自然563，639-645（2018））。这一发现代表了基因组镶嵌主义的一个新的且功能上重要的方面（Elife; 4：E05116（2015）），它通过新鉴定的分子靶标具有真正的治疗潜力。的确，我们发现SGR作用于淀粉样蛋白前体蛋白（APP）的AD基因，会产生数千种不同形式的APP，其中一些富含AD或独有的APP。迄今为止对与AD相关的APP基因变异包括拷贝数变化（CNV）和至少11种单核苷酸变化（SNV），这些变化（SNV）以前在农场AD中被报道为致病性，但在SOD上出现了SOD和Mosaically sad s sad;这些变化是从未切除的神经元中存在的。 SGR利用转录RNA上的逆转录酶（RT）活性，结合DNA链破裂和APP基因转录，产生了双链DNA，并恢复为基因组，形成了“基因组CDNA”（GENCDNAS）（GENCDNAS）。这些已发表的数据促进了当前建议将构建的科学基础，以检验改变SGR（涉及大脑特异性逆转录酶）的假设，在功能上有助于AD并影响多个基因，从而为AD疗法提供了新的靶标。验证后IRB批准的和被识别的大脑样本将与未解决的对照组进行比较，而IACUC批准的动物实验将模拟SGR及其与AD的终点。三个目标将在5年内实现。 AIM 1将定义APP GencDNA多样性的分子神经生物学，并确定AD大脑中增强的新SGR基因。 AIM 2将确定SGR基因在AD脑和模型系统中的表达和功能。 AIM 3将确定负责RT SGR活性的基因和广告大脑内的基因。因此，该提案将通过新型的SGR机制开放新的vistas，并确定用于治疗AD的新治疗靶标。