Identify the target proteins of one ADC-specific and two SCC-specific pfeRNAs and investigate the mechanisms underlying the pfeRNA-protein interaction.

鉴定一种 ADC 特异性 pfeRNA 和两种 SCC 特异性 pfeRNA 的靶蛋白，并研究 pfeRNA-蛋白质相互作用的机制。

• 批准号: 10579497
• 负责人: Yuping Mei
• 金额: $ 8.19万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579497
• 关键词: Adenocarcinoma; Antibodies; Automobile Driving; Benign; Binding; Biological; Biological Assay; Biological Markers; Biology; Biopsy; Biotin; Cancer Etiology; Cells; Cessation of life; Characteristics; Clinical; Clinical Data; Computer software; Cytoplasm; Data; Data Set; Development; Diagnosis; Disease; Ectopic Expression; Elements; Fluorescence Resonance Energy Transfer; Fluorescent in Situ Hybridization; Fractionation; Health; Histologic; Human; Immunoprecipitation; Immunotherapy; In Vitro; Knowledge; Label; Liquid Chromatography; Lung; Lung nodule; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Nuclear; Oligonucleotides; Oncogenic; Patients; Pattern; Plasma; Play; Prognosis; Protein Inhibition; Proteins; Publications; RNA-Binding Proteins; Research; Role; Sensitivity and Specificity; Solid; Specific qualifier value; Specificity; Squamous cell carcinoma; Structure of parenchyma of lung; Survival Rate; Tertiary Protein Structure; Testing; Tissues; United States; biomarker validation; deep sequencing; improved; knock-down; mutant; novel; novel therapeutic intervention; protein activation; protein complex; protein expression; protein function; tandem mass spectrometry; targeted treatment; tumorigenesis

Project Summary: Lung cancer continues to be a significant health burden in the U.S. Thus, a functional understanding of the critical molecules during NSCLC oncogenesis will enhance our knowledge of its malignant transformation, and allow novel therapeutic strategies. We have recently identified critical roles of protein function effector sncRNAs (pfeRNAs) in the tumorigenesis and differentiation of NSCLC, have described their functions in the basic biology of NSCLC, and have elucidated their structural and functional features. We have identified eight pfeRNAs as promising non-invasive biomarkers using sncRNAs deep sequencing by analyzing 108 biospecimens, including (i) plasma from healthy controls, (ii) plasma from patients with Stage I/II NSCLC with matched biopsy-proven NSCLC tissue as well as histologically normal adjacent lung tissue, and (iii) plasma from patients with both biopsy-proven benign and malignant lung nodules. We have already validated these biomarkers in 352 clinical biospecimens, including 77 healthy controls, 44 patients with benign disease, and 231 patients with malignant lung nodules. These eight pfeRNAs were able to: (1) to differentiate patients with or without pulmonary nodules, with a sensitivity and specificity up to 98.1% and 100%, respectively; (2) to differentiate patients who had malignant versus benign pulmonary nodules, with a sensitivity and a specificity up to 78% and 78.8%, respectively. Furthermore, we identified a pfeRNA is ADC-specific and two pfeRNAs are SCC-specific. Besides, we have confirmed functional analyses of these three pfeRNAs one by one and identified their roles in the primary biological activities of ADC, SCC, and HBE cells in vitro. In addition, we specified the cellular distribution of these three pfeRNAs by fluorescence in situ hybridization (FISH) assay. The data strongly suggest that these three pfeRNAs play critical roles in tumorigenesis and cancer development of NSCLC. Thus, in this project, we will identify the target proteins of these three pfeRNAs and investigate the mechanisms underlying the interaction with the target proteins. This project will provide new evidence on NSCLC oncogenesis.

项目概要： 肺癌在美国仍然是一个重大的健康负担，因此，对肺癌的功能性理解 NSCLC 肿瘤发生过程中的关键分子将增强我们对其恶性转化的了解，并且 允许新的治疗策略。 我们最近发现了蛋白质功能效应器 sncRNA (pfeRNA) 在肿瘤发生中的关键作用 以及 NSCLC 的分化，描述了它们在 NSCLC 基础生物学中的功能，并 阐明了它们的结构和功能特点。我们已经确定了 8 种有前景的非侵入性 pfeRNA 通过分析 108 个生物样本，包括 (i) 来自健康人的血浆，使用 sncRNA 深度测序来确定生物标志物 对照，(ii) 来自 I/II 期 NSCLC 患者的血浆以及匹配的活检证实的 NSCLC 组织以及 组织学正常的邻近肺组织，以及 (iii) 来自经活检证实为良性和 恶性肺结节。我们已经在 352 个临床生物样本中验证了这些生物标志物，包括 77 名健康对照者、44 名良性疾病患者和 231 名恶性肺结节患者。这些 八种 pfeRNA 能够：(1) 区分有或没有肺结节的患者，并且具有敏感性 特异性高达 98.1% 和 100%； (2) 区分恶性与恶性患者 良性肺结节的敏感性和特异性分别高达 78% 和 78.8%。此外， 我们确定了一个 pfeRNA 是 ADC 特异性的，两个 pfeRNA 是 SCC 特异性的。此外，我们已经确认 对这三个pfeRNA进行一一功能分析，并确定它们在初级生物学中的作用 ADC、SCC 和 HBE 细胞的体外活性。此外，我们还指定了这三个的细胞分布 通过荧光原位杂交 (FISH) 测定 pfeRNA。数据强烈表明这三 pfeRNA 在 NSCLC 的肿瘤发生和癌症发展中发挥着关键作用。因此，在这个项目中，我们将 鉴定这三种 pfeRNA 的靶蛋白并研究相互作用的机制 与目标蛋白。该项目将为非小细胞肺癌的肿瘤发生提供新的证据。