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Unfolded Protein Response Activation as a Determinant of the Host Response to M. tuberculosis

未折叠蛋白反应激活是宿主对结核分枝杆菌反应的决定因素

基本信息

批准号：
10679815
负责人：
Ryan Harold Finethy
金额：
$ 7.38万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679815
关键词：
ATF6 gene Antibiotics Bacteriology Bar Codes Bone Marrow Cells Cellular Stress Chemicals Chronic Communication DNA Data Development Disease Disease Outcome Disease Progression Endoplasmic Reticulum Ensure Environment Exhibits Flow Cytometry Genetic Genetic Transcription Genetic Variation Genotype Growth Heterogeneity Homeostasis Human Immune response Immunity Immunology Impairment Inbred Strains Mice Inbreeding Individual Infection Inflammation Inflammatory Inflammatory Response Lung Macrophage Massachusetts Mouse Strains Mus Mycobacterium tuberculosis Myelogenous Outcome Pathogenesis Pathologic Pathology Pathway interactions Patients Persons Population Population Heterogeneity Predisposition Production Proteins Recombinants Regulation Reproducibility Research Research Personnel Role Running Scientist Shapes Signal Pathway Signal Transduction Source Stimulus System Techniques Technology Testing Therapeutic Intervention Tissues Training Tuberculosis Universities Variant Whole Organism burden of illness cohort cytokine defined contribution experience experimental study falls genetic approach human disease improved individual response inhibitor insight medical schools novel strategies novel therapeutic intervention pathogen programs pulmonary function response single-cell RNA sequencing skills success targeted treatment therapy development tool

项目摘要

It is estimated that roughly 10 million people fall ill with TB annually. Even when successfully cured with antibiotics, TB patients often suffer from permanently impaired lung function resulting from infection associated inflammation. Host directed therapies that limit nonproductive inflammation represent a promising tool to improve disease outcomes. Development of these therapies has been hindered by the extent of heterogeneity observed in individual responses to Mtb infection. To overcome this limitation, novel approaches must be utilized to understand the pathways underlying these variable outcomes. The applicant proposes the use of the genetically diverse collaborative cross (CC) panel of inbred recombinant mouse strains to characterize the features underlying variable responses to infection. Preliminary studies leveraging the diversity of the CC founder strains revealed that variability in unfolded protein response (UPR) activity may underlie the heterogeneity in immune responses to Mtb infection. The UPR is a mechanism for ensuring endoplasmic reticulum homeostasis and consists of three distinct signaling pathways that initiate complementary responses. The activity of these pathways is influenced by a variety of cell stress, homeostatic, and pathogen sensing pathways, emphasizing the UPRs identity as a convergence point downstream of many potential sources of host variation. This proposal aims to detail the contribution of UPR activity to myeloid responses to Mtb and to determine the feasibility of targeting the individual UPR pathways for therapeutic intervention. The experiments proposed in aim 1 will identify downstream correlates of UPR activity during infection and assess the contribution of the UPR pathways to transcriptional response heterogeneity using single cell RNAseq technology. The studies described in aim 2 will characterize the consequences of chemical and genetic inhibition of UPR pathways on macrophage functions during Mtb infection. Aim 3 will assess the impact of myeloid UPR pathway activity on disease progression following pulmonary Mtb infection using a combination of genetics- and inhibitor- based approaches. Together, these studies will provide insights regarding immune response heterogeneity and the contribution of the UPR pathways to Mtb infection outcomes. The applicant will carry out the proposed studies as part of the Sassetti research group at the University of Massachusetts Chan Medical School. This environment will provide them with the facilities necessary to complete their studies, and input from a collaborative group of scientists with expertise in relevant fields including immunology and bacteriology. By completing the proposed studies, the applicant will gain experience in a variety of experimental techniques, including single cell RNAseq, and flow cytometry. Additionally, through the training detailed in the proposal, the applicant will develop the professional and communication skills necessary for success as an independent researcher. Together, the studies and training proposed within this application will provide the applicant with the skills and experience to run an independent research program.

据估计，每年约有1000万人罹患结核病。即使成功地治愈了