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

项目摘要 该提案的目标是研究逆转录转座子作为免疫原性分子的重要来源 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尚未充分研究的领域。 我开创了从基因组序列中检测反转录转座子的方法，以确定它们在基因组中的作用。 人类大脑和癌症。在这次申请中，我将在我早期成功的基础上开发其他创新的 方法，并将其应用于反转录转座子的免疫学影响的研究。具体而言，这一提议是 发现反转录转座子衍生分子（RDM）的起源以及 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。逆转座子 已经被认为是重要的进化过程和孟德尔疾病的原因; 然而，我们提出了一个新的观点，这些内源性的追溯元素，这表明，这些通常 被抑制的驯化剂被重新激活，产生可能被认为是外来的RDM 分子，从而引起免疫反应模仿其古老的外源性身份，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， 体细胞逆转录转座子动员和其他突变的增加率，表明相应的 各种形式的RDM的增加的负载（例如，胞质ss/dsRNA、cDNA和新肽）， 病理生理学特别是，我们专注于仔细检查逆转录转座子衍生的RNA，产生新的， 由改变的剪接引起的肽（例如，外显子或基因-反转录转座子融合）或通过突变， 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的方法，这项研究将建立一个方法， 框架，以揭示景观的年龄依赖性反转录转座子活动和丰富的RDMS中， 各种人体组织作为基础，在这个新兴的调查领域取得进一步的发现。 它还将表征与分子/病理学/临床参数和基础 机制等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 人类健康和疾病提供有效治疗的基础，以改善人类的生活和健康。

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.