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

阿尔茨海默病中逆转录酶依赖性基因多样化机制的改变

• 批准号: 10509210
• 负责人: JEROLD CHUN
• 金额: $ 1.68万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 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/10509210
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease therapeutic; Amyloid beta-Protein Precursor; Brain; Chromosomal Instability; DNA strand break; Data; Disease; Elements; Gene Dosage; Gene Proteins; Genes; Genetic Heterogeneity; Genetic Recombination; Genetic Transcription; Genomic Instability; Human; Human Genome; Mediator of activation protein; Neurodegenerative Disorders; Neurons; Nuclear; Proteins; RNA; RNA Viruses; RNA-Directed DNA Polymerase; Reverse Transcription; Site; Training; Training Programs; age related neurodegeneration; base; endonuclease; experience; falls; human disease; therapeutic target; tumor progression; virtual

PROJECT SUMMARY/ABSTRACT Somatic gene recombination (SGR) may increase gene copy number and diversity of disease-relevant genes that contribute to age-related neurodegeneration. The proposed SGR mechanism requires gene transcription, reverse transcription of RNA by an endogenous reverse transcriptase (RT), and DNA strand breaks at sites that enable retro-insertion. However, detailed studies on endogenous reverse transcriptase activity in the normal and diseased human brain is virtually unknown. Furthermore, the identity and possible diversity of endogenous reverse transcriptase genes in the human brain has yet to be defined. A strong candidate is the long interspersed nuclear element, LINE1 (L1), that was long thought to be a dead evolutionary remnant of ancient RNA viruses. There are hundreds of thousands of LINE1 sequences in our human genomes and some are clearly active. Based upon sequence data, each LINE1 element contains a potentially active or activatable endogenous reverse transcriptase gene that encodes a likely RT protein, ORF2p, with reverse transcriptase and endonuclease activities. LINE1 is a known mediator of global chromosomal instability, genomic instability, and genetic heterogeneity and has been implicated in the progression of cancer, aging, and multiple neurodegenerative diseases. Candidate Juliet Nicodemus’ project and training program will fall within the parental R01’s Aim 3, and we added additional granularity for this supplement as part of her focused pursuit of Aim 3, as well as to enable optimal training experiences. She will pursue the central hypothesis that diverse forms of functional reverse transcriptases differ in the normal and AD human brain.

项目总结/摘要 体细胞基因重组（SGR）可以增加基因拷贝数和疾病相关基因的多样性 导致与年龄相关的神经退化所提出的SGR机制需要基因转录， 通过内源性逆转录酶（RT）逆转录RNA，并且DNA链在 启用反向插入。然而，对正常人内源性逆转录酶活性的详细研究， 和患病的人脑几乎是未知的。此外，内源性的特性和可能的多样性 人类大脑中的逆转录酶基因尚未被确定。一个强有力的候选人是长穿插 核元件LINE 1（L1），长期以来被认为是古代RNA病毒的死亡进化残留物。 人类基因组中有数十万个LINE 1序列，其中一些显然是活跃的。 基于序列数据，每个LINE 1元件含有潜在活性或可活化的内源性反向 一种转录酶基因，编码一种可能的RT蛋白，ORF 2 p，具有逆转录酶和核酸内切酶 活动LINE 1是已知的整体染色体不稳定性、基因组不稳定性和遗传学不稳定性的介质。 异质性，并与癌症、衰老和多种神经退行性疾病的进展有关。 疾病候选人朱丽叶尼哥底母的项目和培训计划将属于父母R 01的目标3， 作为她对目标3的集中追求的一部分，我们为这个补充增加了额外的粒度， 最佳的培训体验。她将继续研究中心假设，即不同形式的功能性逆转 转录酶在正常和AD人脑中不同。