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

大脑慢性炎症是衰老过程的一个标志，并促进许多大脑的进展 疾病。令人信服的证据表明，健康的可食用植物对正常有重要的生理作用 并能防止神经炎性反应过程。然而，大脑中的机械学研究已经 主要集中在可食用植物的单个或个别因素上，这些因素很可能不代表结果 由多种因素产生，这些因素是每天食用的健康饮食中提供的。 最近，一种名为外周体样纳米颗粒(ELN)的微小纳米颗粒已经从许多 可食用的植物。ELN由脂类、蛋白质和RNA组成。我们已经证明，ELN就像益生元一样， 被肠道细菌吸收，导致抑制小鼠结肠炎。然而，这些可食用植物是否- 衍生的纳米颗粒对大脑是否有直接作用尚不清楚。 在这项研究中，我们将提供细胞和分子方面的见解，了解ELN如何通过一种 肠道-脑轴通过靶向有利于大脑的小胶质细胞。这个提议不可或缺的一点是使用 小鼠衰老模型，研究有助于将ELN开发为潜在的新类别的机制细节 利用益生素来靶向与脑部炎症有关的特定成分。基于这些发现，这是诱人的 推测至少一些脑部抗炎疗法的临床情况可以通过以下方式改善 依赖一种或多种可食用植物来源的ELN的干预措施。这一发现亟待实验 确认，这是我们在本提案中建议调查的内容。从临床应用的角度来看 作为概念验证，在这项研究中，我们的假设是大蒜ELN(GaELN)携带的多种因素 同时靶向小胶质细胞，抑制老龄小鼠脑部炎症。这将在 一种模拟人类衰老过程的小鼠衰老模型。检验我们假设的计划概述为三个部分 明确的目标。我们提出的研究将确定：(1)确定和评估大蒜ELN(GaELN) 磷脂酸(PA)刺激结合钙调素(CaM)的BASP1域(S)阻止c-myc介导 老龄小鼠的脑炎症反应；(2)评估GaELN NC-sRNA21是否参与脑抑制 炎症通过促进c-myc-nick以Rab11a依赖的方式转运到外切体中；以及 (3)评价GaELN是否诱导免疫耐受小鼠向分泌CyLD+外切体转变。 在完成这项拟议的研究后，这项研究将导致确定新的治疗靶点和 潜在的基于ELN的干预措施用于治疗脑部炎症。此外，研究结果将提供一个基础 为了进一步研究口服从不同植物中分离出来的定制ELN是否会有 预防或治疗慢性炎症性脑疾病的协同/相加效应。因此， 这项研究是一项高度翻译的研究，旨在寻找治疗脑部炎症的新靶点。

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.