Mechanism for endogenous retroelements to mimic ancient exogenous identities in aging and diseased human tissue

内源性逆转录因子在衰老和患病人体组织中模仿古代外源特性的机制

• 批准号: 10002836
• 负责人: Eunjung Alice Lee
• 金额: $ 265.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10002836
• 关键词: Aging; Area; Brain; Cells; Cellular Immunity; Clinical; Code; Complementary DNA; Disease; Double-Stranded RNA; Etiology; Foundations; Functional disorder; Genes; Genome; Genomics; Goals; Health; Human; Immune System Diseases; Immune response; Immunologics; Life; Malignant Neoplasms; Mendelian disorder; Methodology; Methods; Molecular; Mutation; Pathogenesis; Pathologic; Peptides; Process; Proteins; RNA; RNA Splicing; Research; Retroelements; Retrotransposon; Role; Shapes; Somatic Mutation; Source; Tissues; Treatment Efficacy; Work; age related; human disease; human tissue; immunogenic; improved; innovation; insight; novel; novel marker; novel therapeutics; success

Project Summary The goal of this proposal is to investigate retrotransposons as a significant source of immunogenic molecules in aging and diseased human tissues. This is an important but understudied area of human genomic research. I have pioneered methods to detect retrotransposons from genome sequences to determine their role in the human brain and in cancer. In this application, I will build on my earlier success to develop other innovative methods and apply them to the study of immunological impact of retrotransposons. Specifically, this proposal is to discover the origins of retrotransposon-derived molecules (RDMs) and the functional consequences of RDMS in pathogenesis to provide a mechanistic basis for novel therapeutics or biomarkers. Retrotransposons have been recognized as important to evolutionary processes and to the causes of Mendelian disorders; however, we propose a new perspective on these endogenous retroelements, suggesting that these normally suppressed domesticated agents are reactivated, producing RDMs that may be considered as foreign molecules, thus causing immunologic responses mimicking their ancient exogenous identities, especially in aging and diseased tissue. Increasing evidence, including our own work, shows that with aging, there is an increasing rate of somatic retrotransposon mobilization and other mutations, suggesting a corresponding increased load of various forms of RDMs (e.g., cytosolic ss/dsRNA, cDNA, and neo-peptides) contributing to pathophysiology. In particular, we focus on scrutinizing retrotransposon-derived RNA that produces neo- peptides caused by altered splicing (e.g., exonization or gene-retrotransposon fusion) or by mutations in protein-coding sequences of retrotransposons. Building upon my expertise in retrotransposons, somatic mutations, and splicing using a genomic and single-cell approach, this study will build a methodological framework to reveal the landscape of age-dependent retrotransposon activity and the abundance of RDMS in various human tissues as the foundation upon which to achieve further findings in this nascent field of inquiry. It will also characterize RDMs associated with molecular/pathological/clinical parameters and underlying mechanisms. This project will support my long-term research goal of defining the role of retrotransposons in human health and disease to provide the basis for effective therapeutics to improve human life and health.

项目摘要 这项提议的目标是研究逆转座子作为免疫原分子的一个重要来源。 在衰老和患病的人体组织中。这是人类基因组研究中一个重要但研究不足的领域。 我开创了从基因组序列中检测反转录转座子的方法，以确定它们在 人类的大脑和癌症。在这个应用程序中，我将在我先前成功的基础上开发其他创新的 方法并应用于反转录转座子对免疫学影响的研究。具体地说，这项建议是 为了发现反转录转座子衍生分子(RDM)的起源和它的功能后果 RDMS在发病机制中的作用，为新的治疗方法或生物标志物提供机制基础。反转录转座子 已经被认为对进化过程和孟德尔病症的原因很重要； 然而，我们对这些内源性逆转录因子提出了一个新的视角，认为这些通常 被抑制的驯化因子被重新激活，产生可以被认为是外来的RDM 分子，从而引起模仿它们古老的外源身份的免疫反应，特别是在 老化和病变的组织。越来越多的证据，包括我们自己的工作，表明随着年龄的增长， 体细胞反转录转座子动员和其他突变的比率增加，表明相应的 各种形式的RDMS(如胞质ss/dsRNA、cDNA和新多肽)的负荷增加有助于 病理生理学。特别是，我们专注于仔细研究反转录转座子衍生的RNA，它产生新的- 由改变剪接引起的多肽(例如，外切或基因-反转录转座子融合)或由 反转录转座子的蛋白质编码序列。基于我在反转录转座子方面的专业知识， 突变和剪接使用基因组和单细胞方法，这项研究将建立一种方法论 揭示年龄依赖反转录转座子活性和RDMS丰度的框架 各种人体组织作为在这个新生的研究领域取得进一步发现的基础。 它还将表征与分子/病理/临床参数和潜在因素相关的RDM 机制。这个项目将支持我的长期研究目标，即确定反转录转座子在 为人类健康和疾病提供有效治疗的基础，改善人类的生活和健康。