权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting microbially-derived juvenile protective factors to resolve neuroinflammation and delirium

针对微生物衍生的青少年保护因子来解决神经炎症和谵妄

基本信息

批准号：
9977764
负责人：
Niccolo Terrando
金额：
$ 16.1万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977764
关键词：
16S ribosomal RNA sequencing Acute Address Adolescent Affect Age Aging Alzheimer&apos s Disease Anesthesia procedures Antibiotics Behavior Bone Regeneration Brain Brain Pathology Chronic Clinical Cognitive deficits Communities Complication Cues Data Delirium Dementia Development Disease Elderly Etiology Feces Fracture Functional disorder Germ-Free Goals Health Care Costs Human Impaired cognition Incidence Infection Infiltration Inflammation Inflammatory Intestinal permeability Intestines Knee Knee Fracture Knowledge Laboratories Lead Length of Stay Life Life Expectancy Link Longevity Mediating Microglia Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neurologic Neuronal Plasticity Operative Surgical Procedures Organ Orthopedic Surgery procedures Outcome Pathogenesis Pathologic Patient-Focused Outcomes Patients Perioperative Positron-Emission Tomography Postoperative Complications Postoperative Period Preventive measure Public Health Recovery Research Resources Risk Risk Factors Rodent Sampling Societies System Testing Therapeutic Transplantation Work age effect age related aged aging population bacterial community biobank blood-brain barrier permeabilization brain parenchyma clinically relevant cognitive function cohort effective therapy fecal microbiota fecal transplantation gut microbiome gut microbiota human microbiota improved innovation knee replacement arthroplasty large datasets macrophage metabolomics microbial microbiome microbiota microbiota metabolites mild cognitive impairment mortality mouse model nervous system disorder neurocognitive disorder neuroinflammation neuron loss neurotransmission novel novel strategies novel therapeutic intervention older patient outcome forecast post-operative cognitive dysfunction postoperative delirium prevent protective effect protective factors repaired resilience response

项目摘要

ABSTRACT Postoperative complications such as delirium represent an immense public health challenge that will continue to intensify as life-expectancy and the number of surgeries during a lifespan continue to increase. Despite efforts to optimize preventive measures, the incidence of postoperative delirium can affect up to 87% of older adults, depending on age and surgical procedures, and remains without an effective treatment. Patients with mild- cognitive impairment (MCI) are most at risk for developing postoperative delirium. Even routine surgical procedures such as common knee replacement or fracture repair, may result in life-threatening outcomes including increased risk for long-term cognitive dysfunction. Thus, new therapeutic strategies are urgently needed. Our long-term goal is to define novel Juvenile Protective Factors (JPFs) derived from intestinal microbiota and to determine their capacity to protect against the development and progression of aging-related neurodegenerative and perioperative disorders. The objective here is to compare molecular signatures in intestinal microbiome samples from healthy juveniles and patients at risk for developing postoperative delirium, which includes older adults and adults with MCI. Our central hypothesis is that juvenile-associated intestinal microbiota generate JPFs that confer resiliency to age-associated neuroinflammation and postoperative delirium. This hypothesis will be tested by pursuing 2 specific aims: 1) analyze the bacterial communities and their molecular signatures in juvenile, aged, and MCI fecal samples; and 2) determine the functional impact of different human microbiota communities on postoperative neuroinflammation and delirium-like behavior. The feasibility of collecting and analyzing these large datasets and models has been established in our laboratories by a unique translational team. Our preliminary data provide evidence that specific metabolites, known to protect against neuronal death, are enriched in feces from juvenile mice. In this innovative approach, we will transplant fecal samples from donor human juvenile, elderly, or MCI patients into germ-free recipient mice in a clinically-relevant surgical mouse model of postoperative neuroinflammation and delirium-like behaviors. Our rationale for the proposed research is that successful completion will demonstrate a novel link between aging-related changes in microbiota and resiliency to postoperative neuroinflammation and cognitive deficits. This work will be significant by improving our understanding of how intestinal microbiota control fundamental brain pathology (ie, neuroinflammation and cogntive decline) that may reveal a unique approach to effective treatment for perioperative neurologic complications.

摘要术后并发症，如谵妄，是一个巨大的公共卫生挑战，将继续下去，随着预期寿命和一生中手术次数的不断增加，尽管努力为了优化预防措施，术后谵妄的发生率可影响高达87%的老年人，这取决于年龄和外科手术，并且仍然没有有效的治疗。轻度- 认知功能障碍（MCI）患者发生术后谵妄的风险最大。即使是常规手术常见的膝关节置换术或骨折修复术等手术可能导致危及生命的结局包括长期认知功能障碍的风险增加。因此，迫切需要新的治疗策略。 needed.我们的长期目标是确定新的少年保护因子（JPF），来自肠微生物群，并确定他们的能力，以防止发展和衰老相关的进展，神经退行性疾病和围手术期疾病。这里的目标是比较分子签名，来自健康青少年和有发生术后谵妄风险的患者的肠道微生物组样品，包括老年人和轻度认知障碍患者。我们的中心假设是，青少年相关的肠道微生物群产生JPF，其赋予与年龄相关的神经炎症和术后谵妄的弹性。这一假设将通过追求2个具体目标进行测试：1）分析细菌群落及其在青少年，老年人和MCI粪便样品中的分子特征;和2）确定不同的功能影响，人类微生物群群落对术后神经炎症和谵妄样行为的影响。的可行性收集和分析这些大型数据集和模型已经在我们的实验室建立了一个独特的翻译团队我们的初步数据提供的证据表明，特定的代谢物，已知的保护，神经元死亡，在幼年小鼠的粪便中富集。在这种创新方法中，我们将移植粪便将来自供体人类青少年、老年人或MCI患者的样品在临床相关的术后神经炎症和谵妄样行为外科小鼠模型。我们的理由是，这项研究的成功完成将证明与衰老相关的变化之间存在一种新的联系，微生物群和术后神经炎症和认知缺陷的弹性。这项工作将具有重大意义通过提高我们对肠道微生物群如何控制基本脑病理学的理解（即，神经炎症和认知能力下降），这可能揭示了一种有效治疗围手术期神经系统并发症。