Targeting non-coding RNAs as host-directed drug therapy for tuberculosis

靶向非编码 RNA 作为宿主导向的结核病药物治疗

• 批准号: 10612779
• 负责人: Reto Guler
• 金额: $ 13.16万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-19 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612779
• 关键词: Affect; Africa; African; African ancestry; Antibiotic Therapy; Antimycobacterial Agents; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Automobile Driving; Bioinformatics; Biology; Cessation of life; Code; Communicable Diseases; Data; Development; Disease; Drug Targeting; Elements; Epigenetic Process; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genome; Genotype; Goals; Growth; Heritability; Heterogeneity; Host Defense; Host resistance; Human; Immune response; Investigation; Knowledge; Macrophage; MicroRNAs; Multidrug Resistance Induction; Mycobacterium tuberculosis; Outcome; Partner in relationship; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Predisposition; Public Health; Publishing; Quantitative Trait Loci; RNA; Research; Resources; Role; Sampling; Shapes; Site; South Africa; South African; Southern Africa; System; Systems Biology; Techniques; Testing; Transcript; Tuberculosis; Uganda; Untranslated RNA; Validation; Variant; antimicrobial; chronic infection; cohort; design; diagnostic biomarker; differential expression; gene interaction; genetic architecture; genetic variant; human disease; in silico; inter-individual variation; knock-down; loss of function; monocyte; multidimensional data; mycobacterial; novel; novel therapeutic intervention; pathogen; resilience; response; targeted delivery; transcriptome; transcriptomics; treatment strategy; tuberculosis treatment

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), causes 1.6 million deaths per mated to be infected with Mtb. There is an urgent need to develop new treatment approaches. In this project, we aim to investigate the role of the host non-coding RNA (ncRNA) landscape in driving susceptibility to tuberculosis (TB) across two study sites in Africa (Cape Town, South Africa and Kampala, Uganda). Focusing on human primary macrophages, we plan to integrate, using systems biology approaches, genetic architecture with the coding and non-coding gene expression landscape of response to Mtb infection. We will identify response expression quantitative trait loci (ReQTLs) for coding genes, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) which will be integrated with coding/non-coding gene expression, co-expression, and deregulation networks to prioritize key variants and regulators orchestrating macrophage response to Mtb infection. The most promising miRNAs and lncRNAs will be validated with orthogonal techniques and considered for functionalization in human macrophages. Here, we will employ loss-of function approaches using antisense oligonucleotides in ex vivo Mtb-infected human monocyte-derived macrophages to evaluate the outcome on intracellular mycobacterial growth and investigation of mechanistic macrophage-specific anti-mycobacterial effector functions. Targeting these identified host miRNAs and lncRNAs could become promising candidates for adjunctive host-directed drug therapy for TB. Our central hypothesis is that a) Mtb hijacks host miRNAs and lncRNAs to establish successful persistence and survival in macrophages, b) that human variation can affect key players and their roles, and c) that an understanding of this can be leveraged to identify, design, implement, and test a novel RNA-based anti-microbial treatment strategy. This hypothesis builds upon our previous unpublished and published data [1] showing that Mtb targets miR-143, miR-365 and lincRNA-MIR99AHG in macrophages to promote mycobacterial growth by fine-tuning expression levels of host genes and is supported by a growing number of other studies [2-16]. Our long-term goal is to develop a host-directed drug system for antisense therapy, specifically inhibiting miRNAs and lncRNAs that are crucially involved in TB pathogenesis. The rationale for this approach would be to create a novel, targeted host-directed RNA-based drug therapy for TB. To achieve this goal, we have assembled a team of experts in ncRNA biology, infectious disease, systems biology, and bioinformatics from multiple sites in Southern Africa, Uganda and the USA.

项目摘要 结核分枝杆菌（MTB），结核病（TB）的致病药物（TB），每人160万人死亡 交配以感染MTB。迫切需要 开发新的治疗方法。在这个项目中，我们旨在调查主机非编码的作用 在非洲的两个研究地点，RNA（NCRNA）景观驱动了对结核病（TB）的敏感性（CAPE） 南非镇和乌干达坎帕拉）。为了关注人类的主要巨噬细胞，我们计划整合， 使用系统生物学方法，具有编码和非编码基因表达的遗传结构 landscape of response to Mtb infection.我们将确定响应表达定量性状基因座（REQTL） 对于编码基因，长的非编码RNA（LNCRNA）和microRNA（miRNA）将与 编码/非编码基因表达，共表达和放松调节网络，以优先考虑关键变体和 调节器策划巨噬细胞对MTB感染的反应。最有希望的mirnas和lncrnas 将通过正交技术进行验证，并考虑在人类巨噬细胞中的功能化。 在这里，我们将使用反义寡核苷酸在离体MTB感染中采用功能丧失方法 人类单核细胞衍生的巨噬细胞评估细胞内分枝杆菌生长和 机械巨噬细胞特异性抗菌效应子功能的研究。针对这些 确定的宿主miRNA和LNCRNA可能成为辅助宿主指导药物的有前途的候选人 结核病治疗。 我们的中心假设是a）mtb劫持托管mirnas和lncrnas以建立成功 巨噬细胞中的持久性和生存，b）人类变异会影响关键参与者及其角色，并且 c）可以利用对此的理解来识别，设计，实施和测试一种新型基于RNA的新型 anti-microbial treatment strategy.该假设建立在我们以前未发布和发布的数据上 [1]表明MTB靶向miR-143，miR-365和lincrna-mir99hg在巨噬细胞中以促进 分枝杆菌通过微调表达水平的宿主基因的表达水平，并受到越来越多的数量的支持 其他研究[2-16]。我们的长期目标是开发一种宿主指导的药物系统，以进行反义疗法， 特别抑制与TB发病机理至关重要的miRNA和LNCRNA。理由 这种方法是为结核病创建一种新型的，有针对性的宿主指导的基于RNA的药物疗法。实现 这个目标，我们召集了NCRNA生物学，传染病，系统生物学和 来自南部非洲，乌干达和美国的多个地点的生物信息学。