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Omics for TB Disease Progression (OTB)

结核病进展组学 (OTB)

基本信息

批准号：
9275342
负责人：
ALAN A ADEREM
金额：
$ 378.07万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-21 至 2018-05-31
项目状态：
已结题

项目摘要

From initial infection to the onset of symptoms, tuberculosis (TB) is a remarkably complex disease. This proposal tests the concept that behaviors of host and pathogen are coordinated by interwoven regulatory networks, and that the outcome of infection (bacterial containment or active disease) is the product of many network-network interactions that vary both spatially and temporally. If so, then perturbing specific networks will both illuminate the topology of the larger network and allow us to define the steps and components critical to infection outcome. Our consortium of two projects and four Cores will test this hypothesis and reveal key features of TB disease progression in an iterative cycle: perturb carefully chosen subnetworks within both MTB and host; collect matched omics data sets; model, predict, and validate with new experiments. Project 1 exploits a vast repository of mutant mice to screen novel candidate genes derived from a unique South African clinical cohort for effects on TB disease progression. Project 2 begins with a novel in vivo genetic screen to identify MTB regulators that affect disease progression in lungs. In each case, once key regulators are identified, we will quantitate and characterize the changes in infected cell types and determine the specific points in disease progression where particular mutants show altered responses. For both projects, we leverage our extensive cache of preliminary data to perform detailed systems analyses of key genes and their predicted regulons using bone marrow macrophages infected ex vivo. We will collect host and MTB transcriptomes and global protein level changes from matched samples. We will also perform condition-specific ChlP-seq on key MTB regulators from within infected macrophages. These data will fuel modeling of both the bacterial and host response networks, predictions from which will drive a new round of mutant evaluation, omics-scale data collection and additional modeling. Our ultimate modeling Aim in this proposal is a novel integrated host/MTB network model, human relevance of which will be validated in primary human macrophages with mutant MTB and relevant host genes dis-regulated via RNAi.

从最初感染到出现症状，结核病是一种非常复杂的疾病。这

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prospective Discrimination of Controllers From Progressors Early After Low-Dose Mycobacterium tuberculosis Infection of Cynomolgus Macaques using Blood RNA Signatures.

使用血液 RNA 特征对食蟹猴进行低剂量结核分枝杆菌感染后早期的控制者与进展者的前瞻性区分。

DOI：
10.1093/infdis/jiy006
发表时间：
2018
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Thompson,EthanG;Shankar,Smitha;Gideon,HannahP;Braun,Jackie;Valvo,Joe;Skinner,JasonA;Aderem,Alan;Flynn,JoAnneL;Lin,PhilanaLing;Zak,DanielE
通讯作者：
Zak,DanielE

Elucidation of host-pathogen protein-protein interactions to uncover mechanisms of host cell rewiring.

DOI：
10.1016/j.mib.2017.07.005
发表时间：
2017-10
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Nicod C;Banaei-Esfahani A;Collins BC
通讯作者：
Collins BC

A computational framework for the inference of protein complex remodeling from whole-proteome measurements.

DOI：
10.1038/s41592-023-02011-w
发表时间：
2023-10
期刊：
NATURE METHODS
影响因子：
48
作者：
Buljan, Marija;Banaei-Esfahani, Amir;Blattmann, Peter;Meier-Abt, Fabienne;Shao, Wenguang;Vitek, Olga;Tang, Hua;Aebersold, Ruedi
通讯作者：
Aebersold, Ruedi

Expression Dysregulation as a Mediator of Fitness Costs in Antibiotic Resistance.

表达失调是抗生素耐药性中适应性成本的介体。

DOI：
10.1128/aac.00504-21
发表时间：
2021-08-17
期刊：
Antimicrobial agents and chemotherapy
影响因子：
4.9
作者：
Trauner A;Banaei-Esfahani A;Gygli SM;Warmer P;Feldmann J;Zampieri M;Borrell S;Collins BC;Beisel C;Aebersold R;Gagneux S
通讯作者：
Gagneux S

Systems proteomics approaches to study bacterial pathogens: application to Mycobacterium tuberculosis.