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.

项目概要/摘要 体细胞基因重组（SGR）可能会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变性的SGR机制需要基因转录， 内源性逆转录酶 (RT) 对 RNA 进行逆转录，DNA 链在以下位点断裂： 然而，对正常情况下内源性逆转录酶活性的详细研究。 此外，内源性的身份和可能的多样性实际上是未知的。 人类大脑中的逆转录酶基因尚未被定义，一个强有力的候选者是长散布的基因。 核元件 LINE1 (L1)，长期以来一直被认为是古代 RNA 病毒死亡的进化残余物。 我们的人类基因组中有数十万个 LINE1 序列，其中一些序列明显活跃。 根据序列数据，每个 LINE1 元件都包含一个潜在活性或可激活的内源性反向序列 编码可能的 RT 蛋白 ORF2p 的转录酶基因，具有逆转录酶和核酸内切酶 LINE1 是已知的整体染色体不稳定、基因组不稳定和遗传的调节因子。 异质性，并与癌症、衰老和多种神经退行性疾病的进展有关 候选人 Juliet Nicodemus 的项目和培训计划将属于父母 R01 的目标 3，以及 作为她对目标 3 的重点追求的一部分，我们为此补充添加了额外的粒度，并能够 她将追求多种形式的功能逆转的中心假设。 正常人脑和 AD 人脑中的转录酶不同。