Transfer RNA sequencing and application to cancer research and clinics

项目摘要 最有效的肿瘤治疗针对多种细胞机制。这项提案将探索一种 使用新开发的高通量在癌症生物学中先前被低估的细胞机制 测序技术。转移RNAs(TRNAs)是读取蛋白质遗传密码的适配分子 生物合成。TRNA对基因表达是必不可少的，基因表达是癌症相关生物标记物的新来源，以及 来自人类和与疾病相关的微生物的表观转录标记的宝库。TRNAs是 在许多癌症中调节失调。由于技术上的困难，tRNA生物学及其在临床癌症中的意义 CARE远远落后于其他基于DNA和RNA的方法。我们最近开发了一项新技术 被称为多重小RNA序列(MSR-SEQ)，这使得首次临床规模的tRNA研究成为可能。 具体目标1将进一步扩大临床样本MSR-SEQ的能力和范围。结直肠癌 在美国，结肠癌(CRC)是与癌症相关的第二大死亡原因。化疗方案还没有 在十年内发生实质性变化，对50%的患者来说是不必要的，在另外30%的患者中是无效的。 目前还没有办法提前对患者进行分类。最近的研究提供了证据表明肠道细菌 可影响结直肠肿瘤的生长和转移。肿瘤与共生肠道的相互作用 微生物为了解结直肠癌的生物学提供了新的视角，并为识别高危患者提供了新的机会 适用于癌症复发和不需要忍受化疗的患者。特定目标2将适用MSR- SEQ筛选来自结直肠癌患者的血液、活检和粪便样本的生物库，并研究结直肠癌小鼠模型 CRC复发。这种独特的生物库与一种新技术的结合有可能改变 对CRC进行治疗，并探索人类疾病中复杂的宿主-微生物相互作用。

Project Abstract Most effective tumor treatments target multiple cellular mechanisms. This proposal will explore a previously under-appreciated cellular mechanism in cancer biology using a newly developed high throughput sequencing technology. Transfer RNAs (tRNAs) are adaptor molecules that read the genetic code for protein biosynthesis. tRNAs are essential for gene expression, an emerging source of cancer-related biomarkers, and a treasure trove of epitranscriptomic marks from both human and disease-associated microbes. tRNAs are dysregulated in many cancers. Due to technical difficulties, tRNA biology and its implications in clinical cancer care have lagged far behind other DNA and RNA-based approaches. We recently developed a new technology called Multiplex Small RNA-seq (MSR-seq) which makes feasible for the first time clinical-scale tRNA studies. Specific Aim 1 will further expand the capability and scope of MSR-seq for clinical samples. Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. Chemotherapy regimens have not substantively changed in a decade, are unnecessary for 50% of patients, and ineffective in another 30%. Currently there is no way to categorize patients ahead of time. Recent studies provide evidence that gut bacteria can influence growth and metastasis of colorectal tumors. Interactions between tumors and commensal gut microbes provide a new lens to understand the biology of CRC and a new opportunity to identify patients at risk for cancer recurrence and patients who have no need to endure chemotherapy. Specific Aim 2 will apply MSR- seq to screen a biobank of blood, biopsy, and stool samples from CRC patients, and to study a murine model of CRC recurrence. This combination of a unique biobank with a new technology has potential to transform how CRC is treated and explores the complex host-microbe interactions in a human disease.