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

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.

大脑慢性炎症是衰老过程的标志，并促进许多大脑疾病的进展。 疾病令人信服的证据表明，健康的可食用植物对正常的生长发育具有重要的生理作用。 大脑功能，并可以防止神经炎症过程。然而，对大脑的机械研究 主要集中在可食用植物的单一或个别因素，这很可能不代表结果 由多种因素产生，这些因素在每天消耗的健康饮食中提供。 最近，一种被称为外泌体样纳米颗粒（ELN）的微小纳米颗粒已经从许多人中分离出来。 食用植物ELN由脂质、蛋白质和RNA组成。我们已经证明ELN和益生元一样， 被肠道细菌吸收，从而抑制小鼠结肠炎。然而，这些可食用的植物- 衍生的纳米粒子对大脑有直接影响尚不清楚。 在这项研究中，我们将提供细胞和分子的见解，如何ELN调节神经免疫功能，通过 通过靶向有益于大脑的小胶质细胞来调节肠-脑轴。与此建议不一致的是使用一个 小鼠衰老模型，以研究机制细节，这将有助于开发ELN作为一个潜在的新类别 益生元的目标是参与大脑炎症的特定成分。基于这些发现， 推测至少一些脑抗炎治疗剂的临床特征可以通过 依赖于一种或多种可食用植物衍生ELN的干预措施。这一发现迫切需要实验 确认，这就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， 靶向小胶质细胞，同时抑制老年小鼠脑炎症。这将在 一种模拟人类衰老过程的小鼠衰老模型。测试我们假设的计划概述在三个 明确的目标。我们的研究将确定：（1）确定和评估大蒜ELN（GaELN）是否 磷脂酸（PA）刺激的BASP 1结构域结合钙调蛋白（CaM），阻止c-MYC介导的 （2）评估GaELN nc-sRNA 21是否有助于抑制老年小鼠的脑炎症; 通过以Rab 11 a依赖性方式增强c-MYC-nick转运到外泌体中来抑制炎症;以及 (3)评估GaELN是否诱导转换为具有免疫耐受货物的CYLD+外泌体的分泌。 在完成这项拟议的研究后，该研究将导致确定新的治疗靶点， 潜在的基于ELN的干预治疗脑炎症。此外，调查结果将为 为了进一步研究口服从不同植物分离的定制ELN是否会有 在预防或治疗慢性炎性脑相关疾病中的协同/相加作用。因此，我们认为， 这项研究是一项高度转化的研究，旨在寻找脑炎症的新治疗靶点。

项目成果

Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells.

• DOI: 10.4049/jimmunol.1203170
• 发表时间: 2013-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Deng ZB;Zhuang X;Ju S;Xiang X;Mu J;Liu Y;Jiang H;Zhang L;Mobley J;McClain C;Feng W;Grizzle W;Yan J;Miller D;Kronenberg M;Zhang HG
• 通讯作者: Zhang HG

Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages.

• DOI: 10.18632/oncotarget.8361
• 发表时间: 2016-05-03
• 期刊: Oncotarget
• 作者: Teng Y;Mu J;Hu X;Samykutty A;Zhuang X;Deng Z;Zhang L;Cao P;Yan J;Miller D;Zhang HG
• 通讯作者: Zhang HG

Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis.

• DOI: 10.1038/onc.2016.229
• 发表时间: 2017-02-02
• 期刊: Oncogene
• 影响因子: 8
• 作者: Deng Z;Rong Y;Teng Y;Zhuang X;Samykutty A;Mu J;Zhang L;Cao P;Yan J;Miller D;Zhang HG
• 通讯作者: Zhang HG

A Plant Pathogen Type III Effector Protein Subverts Translational Regulation to Boost Host Polyamine Levels.

• DOI: 10.1016/j.chom.2019.09.014
• 发表时间: 2019-11
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Dousheng Wu;Edda von Roepenack-Lahaye;Matthias Buntru;Orlando de Lange;Niklas Schandry;Alvaro L Perez Quintero;Z. Weinberg;Tiffany M. Lowe-Power;B. Szurek;A. Michael;C. Allen;S. Schillberg;T. Lahaye

Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles.

• DOI: 10.1002/mnfr.201300729
• 发表时间: 2014-07
• 期刊: Molecular nutrition & food research
• 影响因子: 5.2
• 作者: Mu J;Zhuang X;Wang Q;Jiang H;Deng ZB;Wang B;Zhang L;Kakar S;Jun Y;Miller D;Zhang HG
• 通讯作者: Zhang HG