非编码RNA在重大疾病发生发展中的作用机制

Dysregulation of noncoding RNAs (ncRNAs) in various human diseases has been well documented, but the functions of ncRNAs in human diseases, as well as molecular mechanisms underlying, are still incompletely understood. In this research project, we aim to investigate the functions and molecular mechanisms of ncRNAs in human diseases, including infertility and malignant tumors. The project team consists of 5 research groups, which all have a long-standing interest in non-coding RNAs involved in human diseases. We will combine the analyses of genomics, proteomics, transcriptomes and employ various RNA research methods to explore the functions and mechanisms of ncRNAs during the initiation and progression of human diseases, including the systematic studies at biochemistry, cell culture, animal models and human specimens. The specific aims of this proposal are as follows: 1) the functions and mechanisms of PIWI/piRNA regulatory pathways in human male infertility; 2) the functions and mechanisms of ncRNAs in the coevolution between cancer cells and tumor microenvironment; 3) the functions and mechanisms of circRNAs in immune escape. Data generated from this project will reveal the regulatory roles and mechanisms of ncRNAs during germline development and gametogenesis, the interaction between cancer cells and tumor microenvironment, and tumor immune escape, brings molecular targets for diagnosis and treatment of related human diseases, and lays a foundation for the development of RNA-based new drugs in our nation.

非编码RNA表达异常与人类疾病的相关性已被普遍证实，但目前对其在疾病发生发展中的功能机制还了解有限。本申请项目针对重点资助研究方向（三）“非编码RNA在重大疾病发生、发展中的作用机制”，聚焦生殖障碍、恶性肿瘤等重大多发性疾病，组织了5个长期从事疾病相关非编码RNA研究的基础生物学和临床医学研究团队，将利用基因组学、蛋白组学、转录组学及多种RNA研究技术，拟从分子、细胞及个体（动物模型）等多层面，并结合临床样本分析，深入系统地探索1）PIWI/piRNA调控通路在男性不育症发生发展中的功能机制；2）非编码RNA 在癌细胞及其微环境共进化中的功能机制；3）环形RNA在肿瘤免疫逃逸中的功能机制等。研究结果将揭示非编码RNA调控生殖细胞发育分化和配子形成、肿瘤细胞与组织微环境互作以及肿瘤免疫逃逸的作用机制，为相关疾病的诊治提供新方法技术，并为我国基于RNA靶点的创新药物研发奠定基础。

非编码RNA表达异常与人类疾病的相关性已被普遍证实。本项目针对 “非编码RNA在重大疾病发生、发展中的作用机制”，聚焦生殖障碍、恶性肿瘤等重大多发性疾病，组织了5个长期从事疾病相关非编码RNA研究的基础生物学和临床医学研究团队，深入系统地阐析非编码RNA调控生殖细胞发育分化和配子形成、肿瘤细胞与组织微环境互作以及肿瘤免疫逃逸的作用机制，包括揭示了1）PIWI/piRNA调控通路在精子发生和男性不育中的功能机制；2）非编码RNA 在癌细胞及其微环境共进化中的功能机制；3）circRNA在肿瘤免疫逃逸中的功能机制等。项目研究紧密结合基础研究与临床疾病，为相关疾病的诊治提供新方法技术，并为我国基于RNA靶点的创新药物研发奠定基础。. 在本项目的支持下，已发表研究论文39篇（Nature 2020；Science 2022；N Engl J Med 2022；Mol Cell 2020; Nat Cell Biol 2020; Nat Immunol 2021；Immunity 2022 等）、应邀综述6篇（Nat Rev Mol Cell Biol 2022等）。项目组共培养了49名博士研究生毕业取得学位、20名博士后出站，其中多名研究生获得“国家奖学金”，3位项目组青年科研人员分别受聘同济大学、南京医科大学和北京师范大学研究员、独立PI。此外，在项目执行期间，项目组有2项科研成果实现转让，转让金额>2,100万RMB。

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