Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation

可食用外泌体样纳米颗粒预防脑部炎症的机制

• 批准号: 10668525
• 负责人: HUANG-GE ZHANG
• 金额: $ 65.9万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668525
• 关键词: Acids; Affect; Aging; Bacteria; Binding; Biological; Brain; Brain Diseases; CD11 Antigens; Calmodulin; Cell Separation; Cells; Chronic; Clinical; Consumption; Data; Development; Diet; Disease; Edible Plants; Encephalitis; Foundations; Garlic; Health Status; Human; Immune Tolerance; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intervention; Intestines; Knock-out; Knowledge; Lipids; Macrophage; Mediating; Microglia; Modeling; Molecular; Mus; Neuroimmune; Oral; Oral Administration; Pathway interactions; Phosphatidic Acid; Physiological; Physiology; Plants; Prevention; Prevention strategy; Probiotics; Process; Production; Protein Analysis; Proteins; Publishing; RNA; Role; Small RNA; Sorting; Structure of thyroid parafollicular cell; TNF gene; Testing; Therapeutic; Untranslated RNA; aged; aging brain; blood-brain barrier crossing; brain tissue; c-myc Genes; clinical application; cytokine; design; exosome; good diet; gut-brain axis; improved; in vivo; insight; murine colitis; nanoparticle; neuroinflammation; new therapeutic target; prebiotics; prevent; protective effect; protein expression; transcriptome sequencing; translational study; v-myc Gene; Acids; Affect; Aging; Bacteria; Binding; Biological; Brain; Brain Diseases; CD11 Antigens; Calmodulin; Cell Separation; Cells; Chronic; Clinical; Consumption; Data; Development; Diet; Disease; Edible Plants; Encephalitis; Foundations; Garlic; Health Status; Human; Immune Tolerance; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intervention; Intestines; Knock-out; Knowledge; Lipids; Macrophage; Mediating; Microglia; Modeling; Molecular; Mus; Neuroimmune; Oral; Oral Administration; Pathway interactions; Phosphatidic Acid; Physiological; Physiology; Plants; Prevention; Prevention strategy; Probiotics; Process; Production; Protein Analysis; Proteins; Publishing; RNA; Role; Small RNA; Sorting; Structure of thyroid parafollicular cell; TNF gene; Testing; Therapeutic; Untranslated RNA; aged; aging brain; blood-brain barrier crossing; brain tissue; c-myc Genes; clinical application; cytokine; design; exosome; good diet; gut-brain axis; improved; in vivo; insight; murine colitis; nanoparticle; neuroinflammation; new therapeutic target; prebiotics; prevent; protective effect; protein expression; transcriptome sequencing; translational study; v-myc Gene

Brain chronic inflammation is a hallmark of the aging process, and promotes the progression of many brain diseases. Compelling evidence shows that healthy edible plants have important physiological roles for normal brain function and can prevent neuroinflammatory processes. However, mechanistic studies in the brain have primarily focused on single or individual factors from edible plants, which most likely do not represent the results generated from multiple factors that are provided in a healthy diet consumed daily. Recently, a tiny nanoparticle called an exosome-like nanoparticle (ELN) has been isolated from a number of edible plants. ELNs consists of lipids, proteins, and RNAs. We have demonstrated that ELNs, like prebiotics, are taken up by intestinal bacteria, resulting in inhibition of mouse colitis. However, whether these edible plant- derived nanoparticles have a direct effect on the brain is not clear. In this study, we will provide cellular and molecular insight into how ELNs modulate neuroimmune function via a gut-brain axis by targeting microglial cells that benefits the brain. Indispensable to this proposal is the use of a mouse aging model to investigate mechanistic details that will facilitate developing ELNs as a potential new class of prebiotic to target specific components involved in brain inflammation. Based on these findings it is tempting to speculate that the clinical profile of at least some brain anti-inflammation therapeutics can be improved by interventions relying on one or more edible plant-derived ELNs. This finding urgently awaits experimental confirmation, which is what we proposed to investigate in this proposal. From a clinical application standpoint and as proof-of-concept, in this study, our hypothesis is that multiple factors carried by garlic ELNs (GaELN) target to microglial cells simultaneously to inhibit brain inflammation in aged mice. This will be tested in a mouse aging model that mimics human aging process. The plan to test our hypothesis is outlined in three specific aims. Our proposed studies will determine: (1) Determine and evaluate if garlic ELN (GaELN) phosphatidic acid (PA) stimulated BASP1 domain(s) that binds to calmodulin (CaM) prevents c-MYC mediated brain inflammation in aged mice; (2) Evaluate whether GaELN nc-sRNA21 contributes to inhibition of brain inflammation by enhancing the transporting of c-MYC-nick into exosomes in a Rab11a dependent manner; and (3) Evaluate whether GaELN induces a switch to secretion of CYLD+exosomes with immune tolerant cargos. Upon accomplishing this proposed study, the study will lead to identification of new therapeutic targets and potential ELN based interventions for treating brain inflammation. In addition, findings will provide a foundation to further study whether oral administration of customized ELNs isolated from different plants will have a synergistic/additive effect on prevention or treatment of chronic inflammatory brain related diseases. Therefore, this study is a highly translational study aimed at finding new therapeutic targets for brain inflammation.

脑慢性炎症是衰老过程的标志，并促进许多大脑的发展 疾病。令人信服的证据表明，健康的可食用植物对正常具有重要的生理作用 大脑功能并可以防止神经炎症过程。但是，大脑中的机械研究 主要集中于可食用植物的单一因素或个人因素，这很可能不代表结果 是由每天消耗健康饮食中提供的多种因素产生的。 最近，一种称为外泌体样纳米颗粒（ELN）的微小纳米颗粒已从许多 食用植物。 ELN由脂质，蛋白质和RNA组成。我们已经证明了ELN，例如益生元， 被肠道细菌吸收，导致小鼠结肠炎的抑制作用。但是，这些可食用的植物是否 衍生的纳米颗粒对大脑有直接影响。 在这项研究中，我们将提供细胞和分子洞察力，以了解ELN如何通过A调节神经免疫功能 肠脑轴通过靶向有益于大脑的小胶质细胞。该提议必不可少的是使用 小鼠老化模型研究机械细节，以促进将ELN作为潜在的新类 益生元靶向涉及脑部炎症的特定成分。基于这些发现，它很诱人 为了推测至少某些大脑抗炎治疗的临床特征可以通过 依靠一种或多种可食用植物衍生的ELN的干预措施。这一发现紧急等待实验 确认，这是我们建议在本提案中调查的内容。从临床应用的角度来看 作为概念证明，在这项研究中，我们的假设是大蒜ELN（Gaeln）携带的多种因素 靶向小胶质细胞同时抑制老年小鼠的脑炎症。这将在 模拟人类衰老过程的小鼠衰老模型。在三个中概述了检验我们的假设的计划 具体目标。我们提出的研究将确定：（1）确定和评估大蒜ELN（Gaeln）是否是否 磷脂酸（PA）刺激与钙调蛋白（CAM）结合的BASP1结构域可防止C-Myc介导 老年小鼠的脑炎症； （2）评估Gaeln NC-SRNA21是否有助于抑制大脑 通过以Rab11a的方式增强C-Myc-Nick进入外泌体的炎症；和 （3）评估Gaeln是否诱导了具有免疫耐受剂的CyLd+外泌体的分泌。 完成这项拟议的研究后，该研究将导致确定新的治疗靶点和 潜在的基于ELN的干预措施来治疗脑部炎症。此外，发现将为基础提供基础 为了进一步研究，从不同植物中分离出的定制ELN是否具有 对预防或治疗慢性炎症性脑相关疾病的协同/加性作用。所以， 这项研究是一项高度转化的研究，旨在寻找用于脑部炎症的新治疗靶标。