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

基本信息

批准号：
10394428
负责人：
Reto Guler
金额：
$ 13.26万
依托单位：
UNIVERSITY OF CAPE TOWN
依托单位国家：
美国
项目类别：
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/10394428
关键词：
Affect Africa African African ancestry Antibiotic Therapy 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 Lead MicroRNAs Multi-Drug Resistance 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 base chronic infection cohort design diagnostic biomarker differential expression genetic architecture genetic variant human disease in silico inter-individual variation knock-down loss of function macrophage monocyte multidimensional data mycobacterial novel pathogen resilience response targeted delivery transcriptome transcriptomics treatment strategy tuberculosis treatment

项目摘要

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.

项目概要结核分枝杆菌 (Mtb) 是结核病 (TB) 的病原体，每年导致 160 万人死亡。交配感染 Mtb。有一个迫切的需要开发新的治疗方法。在这个项目中，我们的目标是研究主机非编码的作用非洲（开普敦）两个研究地点的 RNA (ncRNA) 景观对结核病 (TB) 易感性的影响南非镇和乌干达坎帕拉）。专注于人类初级巨噬细胞，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对 Mtb 感染的反应情况。我们将识别响应表达数量性状基因座 (ReQTL) 用于编码基因、长非编码 RNA (lncRNA) 和 microRNA (miRNA)，它们将与编码/非编码基因表达、共表达和解除管制网络，以优先考虑关键变异和调节巨噬细胞对结核分枝杆菌感染的反应。最有前途的 miRNA 和 lncRNA 将通过正交技术进行验证，并考虑在人类巨噬细胞中进行功能化。在这里，我们将在体外 Mtb 感染中采用使用反义寡核苷酸的功能丧失方法人单核细胞来源的巨噬细胞评估细胞内分枝杆菌生长的结果机械巨噬细胞特异性抗分枝杆菌效应功能的研究。针对这些确定的宿主 miRNA 和 lncRNA 可能成为辅助宿主导向药物的有希望的候选者结核病治疗。我们的中心假设是 a) Mtb 劫持宿主 miRNA 和 lncRNA 以建立成功的巨噬细胞中的持久性和存活，b) 人类变异可以影响关键参与者及其角色，以及 c) 对此的理解可用于识别、设计、实施和测试一种新型的基于 RNA 的方法抗微生物治疗策略。这个假设建立在我们之前未发表和已发表的数据的基础上 [1]显示Mtb靶向巨噬细胞中的miR-143、miR-365和lincRNA-MIR99AHG以促进通过微调宿主基因的表达水平来控制分枝杆菌的生长，并得到越来越多的支持其他研究[2-16]。我们的长期目标是开发一种用于反义治疗的宿主导向药物系统，特异性抑制与结核病发病机制至关重要的 miRNA 和 lncRNA。理由这种方法将创造一种新型的、靶向宿主的、基于 RNA 的结核病药物疗法。达到为了这个目标，我们组建了一支由 ncRNA 生物学、传染病、系统生物学和来自南部非洲、乌干达和美国多个地点的生物信息学。