Beyond infection: Innate immune receptors as an emerging brake on metastasis

超越感染：先天免疫受体作为新兴的转移制动剂

• 批准号: 9230016
• 负责人: Sneha Prakash Rath
• 金额: $ 4.51万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230016
• 关键词: Adhesions; Apoptosis; BRCA1 gene; Bacterial Infections; Binding; Breast Cancer Cell; Breast Cancer cell line; Breast cancer metastasis; Cancer Biology; Cancer Immunology Science; Cell Culture Techniques; Cell Cycle Progression; Cell Differentiation process; Cell Proliferation; Cells; Cleaved cell; Collaborations; Diabetes Mellitus; Diagnostic; Double-Stranded RNA; Elements; Employee Strikes; Ensure; Enzymes; Gene Expression; Genomic Instability; Goals; Growth; Health; Homeostasis; Human; Immune; Immune system; Immunologic Receptors; Infection; Inherited; Institution; Knock-out; Knockout Mice; Laboratories; Lead; Leadership; Ligase; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mentorship; Messenger RNA; Molecular; Monitor; Mus; Mutation; Names; Natural Immunity; Neoplasm Metastasis; Obesity; Organ; Pathology; Pathway interactions; Phase; Phenotype; Process; Proteomics; RNA; RNA Decay; RNA Viruses; Reporting; Repression; Research; Research Project Grants; Resources; Ribonucleases; Risk; Role; Scientist; Second Messenger Systems; Signal Transduction; Spleen; Testing; Thymus Gland; Time; Training; Tumor Burden; Tumor Suppression; Tumor Suppressor Proteins; Virus; Virus Diseases; Work; abstracting; adipocyte differentiation; base; cancer risk; cancer seeding; cancer therapy; career; cellular targeting; combat; coping; epithelial to mesenchymal transition; feeding; follow-up; forging; human disease; insight; knock-down; malignant breast neoplasm; men; mouse model; novel; novel diagnostics; novel therapeutics; oligoadenylate; pathogen; research study; second messenger; skills; stem; therapeutic target; tool; transcriptome sequencing; tumor progression

BEYOND INFECTION: INNATE IMMUNE RECEPTORS AS AN EMERGING BRAKE ON METASTASIS ABSTRACT Innate immune signaling is a key mammalian defense against pathogens. Importantly, these signaling networks are critically linked to human disease even outside the realm of infections. This facet of innate immunity remains largely elusive and forms the subject of my research. My thesis focuses on the pseudokinase RNase L, which is most strongly activated during infection. RNase L is triggered by 2'-5'-linked iso-RNAs, produced by oligoadenylate synthetases (OASs) upon sensing double-stranded RNA (dsRNA) commonly thought to come from RNA viruses. RNase L is essential for coping with bacterial and viral infections. RNase L is also a major regulator of cell cycle progression, differentiation, and apoptosis, processes often misregulated in cancers. Notably, many RNase L mutations predispose men to an elevated risk of inherited prostate cancer. Moreover, my preliminary results uncover that dampened RNase L expression strongly correlates with increased breast cancer aggressiveness. The effect of RNase L on tumor suppression is striking but its molecular mechanism is unclear. My work identifies the first cellular targets of human RNase L outside infection, tackling a challenge faced since the discovery of RNase L in 1980. Serendipitously, RNase L targets perfectly overlap with those of a well-established tumor-suppressor, miR-200, and one of their common targets is the master regulator of metastasis, ZEB1. These results suggest a direct molecular mechanism for the role of RNase L in controlling metastasis, which I seek to examine during my F99 phase. In addition, I will isolate endogenous dsRNAs, predicted to be elevated in cancers, which can feed into the OAS/RNase L axis. Thus, I will test if OASs are a dsRNA surveillance mechanism against not only viruses but also cancer. This work will uncover the molecular mechanism for a major non-immune function of the OAS/RNase L axis, informing novel diagnostic and therapeutic strategies against metastasis. My thesis initiates me into the emerging field of innate immunity in cancer and seeds my postdoctoral research directions. With rigorous training and an exciting potential to serve human health, I am on a perfect trajectory to launch an independent career at the forefront of cancer immunology.

超越感染：天然免疫受体作为转移的紧急制动器 摘要 先天免疫信号是哺乳动物抵抗病原体的关键。重要的是，这些信号 网络与人类疾病密切相关，甚至在感染领域之外。这方面的先天 免疫力在很大程度上仍然是难以捉摸的，并形成了我的研究课题。我的论文集中在 假激酶RNase L，其在感染期间被最强烈地激活。RNase L是由2 '-5'-linked iso-RNA，由寡腺苷酸合成酶（OAS）在感应双链RNA（dsRNA）时产生 通常认为来自RNA病毒。核糖核酸酶L是对付细菌和病毒所必需的 感染. RNase L也是细胞周期进程、分化和凋亡过程的主要调节剂 在癌症中经常被错误调节。值得注意的是，许多RNase L突变使男性易患以下疾病的风险升高： 遗传性前列腺癌此外，我的初步结果揭示，抑制RNA酶L的表达， 与乳腺癌侵袭性增加密切相关。核糖核酸酶L的抑瘤作用 但其分子机制尚不清楚。我的工作确定了人类RNase的第一个细胞靶点 L外部感染，解决了自1980年发现RNase L以来面临的挑战。偶然发现，RNase L的靶点与一种公认的肿瘤抑制因子miR-200的靶点完全重叠， 常见的靶点是转移的主要调节因子ZEB 1。这些结果表明， RNase L在控制转移中的作用的机制，我试图在我的F99期检查。在 此外，我将分离内源性双链RNA，预测在癌症中会升高，它可以进入细胞内。 OAS/RNase L轴。因此，我将测试OAS是否是一种dsRNA监视机制，不仅针对病毒， 还有癌症这项工作将揭示一个主要的非免疫功能的分子机制， OAS/RNase L轴，为转移的新诊断和治疗策略提供信息。我的论文 让我开始进入癌症先天免疫的新兴领域，并为我的博士后研究奠定了基础。 方向经过严格的训练和为人类健康服务的令人兴奋的潜力，我正处于一个完美的轨道上， 在癌症免疫学的前沿开展独立的职业生涯。