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

项目摘要/摘要 体细胞基因重组(SGR)可以增加疾病相关基因的拷贝数和多样性 这会导致与年龄相关的神经退化。建议的SGR机制需要基因转录， 通过内源性逆转录酶(RT)逆转录RNA，DNA链在 启用追溯插入。然而，对正常人内源性逆转录酶活性的详细研究 而患病的人脑几乎是未知的。此外，内源基因的同一性和可能的多样性 人类大脑中的逆转录酶基因尚未得到定义。一个强有力的候选人是长期穿插的 核素，LINE1(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LINE1序列，其中一些显然是活跃的。 根据序列数据，每个LINE1元件包含一个潜在的活性或可激活的内源性反向 转录酶基因，编码一个可能的RT蛋白，ORF2p，带有逆转录酶和内切酶 活动。LINE1是一种已知的全球染色体不稳定、基因组不稳定和遗传 异质性，并与癌症、衰老和多发性神经退行性变的进展有关 疾病。候选人朱丽叶·尼科德穆斯的项目和培训计划将属于家长R01‘S目标3，以及 我们为本附录添加了额外的粒度，作为她对目标3的专注追求的一部分，以及实现 最佳培训体验。她将坚持核心假设，即不同形式的功能颠倒 正常人脑和阿尔茨海默病人脑的转录酶不同。

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.