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Lead compound discovery from proprietary mycobacterial strains for treatment of PTSD

从专有分枝杆菌菌株中发现用于治疗 PTSD 的先导化合物

基本信息

批准号：
10461571
负责人：
Adam Bohr
金额：
$ 4.22万
依托单位：
MYCOBACTERIA THERAPEUTICS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461571
关键词：
Adult Anti-Inflammatory Agents Anxiety Bacteria Behavioral Assay Biological Assay Bone Marrow Brain Cell Line Cells Chemicals Chronic Colitis Colorado Country Cues Data Dendritic Cells Development Diagnosis Disease Ensure Exposure to Extinction (Psychology)Female Friends Fright Gene Expression Genes Genus Mycobacterium Goals Granulocyte-Macrophage Colony-Stimulating Factor Hippocampus (Brain)Human Immune Immunization Immunophenotyping Impairment Income Individual Inflammation Inflammatory Inflammatory Bowel Diseases Institute of Medicine (U.S.)Interferon Type II Interleukin-1 beta Interleukin-10 Interleukin-12 Interleukin-2 Interleukin-4 Interleukin-6 Interleukin-8 Interleukins Intervention Lead Learned Helplessness Lipopolysaccharides Measures Mediator of activation protein Mental Depression Mental disorders Messenger RNA Microglia Modeling Modernization Mus Neuraxis Outcome Patients Peripheral Pharmacological Treatment Phylogenetic Analysis Post-Traumatic Stress Disorders Preclinical Testing Predisposition Preparation Prevention Prevention Measures Property Rattus Research Risk Risk Factors Selective Serotonin Reuptake Inhibitor Severities Small Business Technology Transfer Research Soil Sprague-Dawley Rats Stress Symptoms Syndrome TNF gene Therapeutic Therapeutic Intervention Trauma Universities base behavioral response chemokine clinical development conditioned fear cytokine depressive symptoms effector T cell expectation immunoregulation in vivo lead candidate mRNA Expression macrophage male meetings microbial monocyte mouse model mycobacterial neuroinflammation novel novel strategies novel therapeutic intervention pathogen patient subsets post-traumatic symptoms preclinical development preclinical study prevent protective effect protein expression response screening socioeconomics stress resilience stressor subcutaneous success systemic inflammatory response therapeutic development

项目摘要

Project Summary Immunoregulation, i.e., balanced expression of regulatory and effector T cells, is thought to be compromised in modern high-income settings due in part to reduced contact with commensal and environmentally derived bacteria, also known as “old friends”. Failed immunoregulation is thought to be one factor contributing to recent increases in stress-related and chronic inflammatory disorders as well stress-related psychiatric disorders in which inflammation is a risk factor, such as depression, anxiety, and posttraumatic stress disorder (PTSD), in high-income countries. One of these “old friends” is Mycobacterium vaccae NCTC 11659, a nonpathogenic, environmental saprophyte with anti-inflammatory and immunoregulatory properties. Immunization in the form of a heat-killed preparation of M. vaccae has been shown to increase stress resilience in mice, as measured by prevention of stress-induced increases in anxiety, prevention of stress-induced exaggeration of spontaneous colitis, and prevention of stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease. Immunization with M. vaccae, when conducted either before or after fear conditioning, has also been shown to enhance fear extinction in a rat model of fear-potentiated startle. In other studies, immunization with M. vaccae has been shown to prevent stress-induced exaggeration of anxiety-like defensive behavioral responses in a rat model of learned helplessness in association with suppression of stress-induced microglial priming and neuroinflammation. However, the extent to which these stress resilience and stress-protective effects generalize to other strains of mycobacteria are not known. In this STTR proposal, we propose to screen, using murine bone marrow-derived dendritic cells (BMDCs), human monocyte-derived macrophages (THP-1 cells), and a microglial cell line (BV2 cells), twenty proprietary strains of environmental mycobacteria for anti-inflammatory and immunoregulatory properties. For screening, we will target strains that meet the following criteria: they can readily be cultivated in isolation; they are not closely related to known mycobacterial pathogens; and they represent distinct lineages spanning the phylogenetic breadth of known mycobacterial diversity (of which there are >150 described mycobacterial strains). We will then screen two lead candidates, using male and female rats, to identify novel strains of mycobacteria with stress-protective effects, as measured by prevention of inescapable stress (IS)-induced increases in anxiety, conditioned fear, and escape deficits, and prevention of stress-induced priming of hippocampal microglia and neuroinflammation. We will also evaluate these strains in models of fear-potentiated startle and cued fear in male and female rats. At the completion of these studies, it is our expectation that we will have identified a single lead strain of mycobacteria that has the best properties for further preclinical testing and clinical development. These results are expected to have an important positive impact for treatment of trauma- and stressor-related disorders because current pharmacological treatments have significant limitations.

项目总结