Targeting age-related neuroinflammation and postoperative cognitive decline: a microbial-based approach

针对与年龄相关的神经炎症和术后认知能力下降：基于微生物的方法

基本信息

批准号：
10577730
负责人：
Laura K Fonken
金额：
$ 48.38万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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：
2020-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577730
关键词：
Address Adult Age Aging Alzheimer&apos s Disease Animals Anti-Inflammatory Agents Bacteria Behavioral Brain Cells Central Nervous System Clinical Cognitive deficits Communication Dementia Development Elderly Environment Exposure to Genus Mycobacterium Goals Human Hygiene Hyperactivity Hypersensitivity Immune Immune response Immune system Immunotherapy Impaired cognition Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-10 Interleukin-4 Laboratories Malignant Neoplasms Mediating Meningeal Mental Depression Microbe Microglia Modeling Modernization Molecular Morbidity - disease rate Neuroimmune Operative Surgical Procedures Pathologic Patients Peripheral Pharmaceutical Preparations Population Postoperative Period Process Quality of life RNA Interference Rattus Research Risk Risk Factors Rodent Role Shapes Signal Pathway Signal Transduction Societies Soil Sterility Stimulus Stress Subcutaneous Injections T-Lymphocyte Therapeutic Therapeutic Uses Toxic effect Work age related age related neuroinflammation aged aging brain aging population commensal microbes immune function immunoregulation improved inflammatory milieu innovation microbial microbial based therapy microorganism mortality neural neuroinflammation novel older patient patient subsets pharmacologic post-operative cognitive dysfunction pre-clinical prevent protective effect response transcriptomics transmission process treatment strategy virtual

项目摘要

Project Summary/Abstract Postoperative cognitive decline (POCD) is a debilitating condition that particularly plagues aged individuals (~40% of elderly surgical patients develop POCD). POCD substantially increases the risk of morbidity, mortality, and the development of Alzheimer’s disease. Inflammation in the brain (“neuroinflammation”), which becomes more excitable or “primed” with age, may cause POCD. Indeed, substantial changes in the immune system occur with age and the immune system communicates with the central nervous system (CNS) and alters the function of local CNS immune cells such as microglia. In modern society, unusually clean conditions decrease exposure to environmental and commensal microorganisms that help shape immunoregulatory circuits. Reintroduction of microorganisms in an overly sterile environment can improve immunoregulation and quell hyperactive inflammatory responses. Despite the therapeutic potential of specific small microbes, few studies have assessed whether microbial-based treatment strategies target the CNS and are effective in aged populations. One such microbe that could benefit neuroinflammation in aging is the widely distributed soil bacterium Mycobacterium vaccae (M. vaccae), which is approved for therapeutic use in humans and improves quality of life in other contexts (allergy and cancer). Thus, the central hypothesis of this proposal is that M. vaccae immunotherapy (three subcutaneous injections) will protect against primed neuroinflammation and cognitive decline in aged rats following surgery. Our preliminary results indicate that M. vaccae immunotherapy has robust and sustained anti- inflammatory activity (+IL-4) in the CNS of aged rats and blocks persistent pro-inflammatory responses (IL-1β) and cognitive deficits following surgery. M. vaccae appears to induce a beneficial (anti-inflammatory) CNS response and redirect the activation state of microglia. M. vaccae enhances immunoregulation in the body through altering T cell populations and may shift the population of T cells accessing the CNS and surrounding meningeal space to elicit changes in the CNS. Thus, this proposal addresses the following specific aims: first, establish whether M. vaccae is a viable pre-clinical target for preventing age-associated POCD; second, identify the CNS-specific mechanisms by which M. vaccae induces a sustained protective shift in the aged neuroimmune environment; and third, establish how M. vaccae communicates its anti-inflammatory signal to the brain. This research is innovative: microbial-based treatments can effectively improve peripheral inflammation, yet there is almost no research investigating whether microbial-based treatments can protect against damaging neuroinflammation. Our overall long-term goals are to elucidate the cellular and molecular mechanisms underlying neuroinflammatory priming; to understand how microglia function transitions toward pathological responses with age; and to determine how these neuroimmune alterations hijack behavioral function.

项目概要/摘要术后认知能力下降 (POCD) 是一种使人衰弱的疾病，尤其困扰老年人（约 40% 的老年手术患者出现 POCD） POCD 大大增加了发病率、死亡率、以及大脑炎症（“神经炎症”）的发展。随着年龄的增长，变得更加兴奋或“启动”，可能会导致 POCD 事实上，免疫系统会发生重大变化。随着年龄的增长，免疫系统会与中枢神经系统 (CNS) 沟通并改变其功能局部中枢神经系统免疫细胞（例如小胶质细胞）在现代社会中，异常清洁的环境会减少暴露。有助于重新引入免疫调节回路的环境和共生微生物。过度无菌环境中的微生物可以改善免疫调节并平息多动症尽管特定小微生物具有治疗潜力，但很少有研究对其进行评估。基于微生物的治疗策略是否针对中枢神经系统并且对老年人群有效。可能对衰老过程中的神经炎症有益的微生物是广泛分布的土壤细菌分枝杆菌母牛分枝杆菌 (M. vaccae)，已被批准用于人类治疗用途，并可改善其他人的生活质量因此，该提案的中心假设是母牛分枝杆菌免疫疗法。（三次皮下注射）将防止老年大鼠引发神经炎症和认知能力下降我们的初步结果表明，母牛分枝杆菌免疫疗法具有强大且持续的抗- 老年大鼠中枢神经系统的炎症活动 (+IL-4) 并阻断持续的促炎症反应 (IL-1β) 和手术后的认知缺陷。母牛分枝杆菌似乎可以诱导有益的（抗炎）中枢神经系统。反应并重新定向小胶质细胞的激活状态，增强体内的免疫调节。通过改变 T 细胞群，并可能改变进入 CNS 和周围环境的 T 细胞群脑膜空间引起中枢神经系统的变化因此，该提案解决了以下具体目标：首先，确定母牛分枝杆菌是否是预防与年龄相关的 POCD 的可行临床前目标；其次，确定母牛分枝杆菌诱导老年神经免疫持续保护性转变的中枢神经系统特异性机制第三，确定母牛分枝杆菌如何将其抗炎信号传递给大脑。研究具有创新性：基于微生物的治疗可以有效改善周围炎症，但几乎没有研究调查基于微生物的治疗是否可以防止损害我们的总体长期目标是阐明细胞和分子机制。潜在的神经炎症启动；了解小胶质细胞功能如何转变为病理性的随年龄变化的反应；并确定这些神经免疫改变如何劫持行为功能。