Engineering bacterially derived immunomodulants:a novel IBD therapeutic approach

工程细菌衍生的免疫调节剂：一种新的 IBD 治疗方法

• 批准号: 8545388
• 负责人: Julie Champion
• 金额: $ 16.15万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545388
• 关键词: Abdominal Pain; Adverse effects; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Automobile Driving; Bacteria; Bacterial Proteins; Biochemical; Biological; Biomedical Engineering; Breathing; Cells; Chemical Models; Chronic Disease; Clinical; Colitis; Cytosol; Destinations; Diarrhea; Disease; Dose; Drug Formulations; Engineering; Ensure; Epithelial; Epithelial Cells; Epithelium; Evolution; Exhibits; Gastrointestinal tract structure; Genetic Models; Goals; Health; Histopathology; Human; Immunological Models; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Kinetics; Ligands; Measures; Modality; Mucous Membrane; Mucous body substance; Mus; Outcome; Pathway interactions; Preparation; Property; Proteins; Signal Pathway; Site; Source; Symptoms; System; Testing; Therapeutic; Therapeutic Effect; Time; Travel; Work; base; cellular engineering; chemical property; crosslink; cytokine; density; design; dosage; enteric pathogen; extracellular; in vivo; inflammatory marker; intracellular protein transport; meetings; mucosal uptake; nanoparticle; novel; novel therapeutic intervention; novel therapeutics; particle; pathogen; physical property; research study; response; small molecule; surface coating; trafficking; uptake

Bioengineering bacterially derived immunomodulants: a novel therapeutic approach to IBD Project Summary The long term goal is to develop novel, effective therapeutics that harness the immunomodulatory properties of bacterial molecules for the treatment of inflammatory bowel disease (IBD). The proposal aims to exploit the evolved ability of intestinal pathogens to control inflammatory related signaling pathways in their host, by adapting bacterial effector molecules as therapeutics. A major challenge in realizing the therapeutic potential of these molecules is the ability to engineer a delivery system capable of delivering protein inside intestinal epithelial cells. The objective of this proposal is to create bacterial protein nanoparticles with the ability to deliver bacterial effector proteins, suppress epithelial inflammation, and attenuate the symptoms of IBD. Key outcomes are: (1) a new, long-needed IBD therapeutic that arrests inflammation at the source; (2) a new therapeutic paradigm that utilizes bacterial immunoregulatory mechanisms and engineers a nanoparticle delivery strategy essential for clinical viability. Three specific aims have been set: Aim 1. Engineer the cellular uptake and trafficking properties of nanoparticles to maximize protein delivery. Bacterial protein nanoparticles will be fabricated with different physiochemical features including size, crosslinking density, targeting ligands, and endosomal escape motifs. Epithelial cells exposed to nanoparticles in vitro will be assessed for particle internalization, endosomal escape, and disassociation into soluble protein. Aim 2. Assess in vitro and exvivo biological response to bacterial protein nanoparticles. Various nanoparticle formulations, including those from Aim 1 as well as particles optimized in this aim for transport through mucus, will be applied to unpolarized and polarized epithelial cells, and ex vivo mucosal preparations at a range of dosages. Functional activity will be measured by mucosal uptake, suppression of immune signaling pathways, and reduced levels of inflammatory cytokines. Aim 3. Determine the therapeutic effect of protein nanoparticles optimized for in vivo delivery on diseased animals. Nanoparticles will be modified via surface coatings to increase their ability to traverse the gastrointestinal tract and target inflamed mucosa. These particles will be administered to mice with induced chemical, immunological and genetic models of colitis and to healthy controls. Clinical parameters, mucosal and systemic inflammatory markers, and histopathology will be tracked over relevant time points.

生物工程细菌得出的免疫调节剂：一种新型的IBD治疗方法 项目摘要 长期目标是开发新颖，有效的治疗剂，以利用 细菌分子用于治疗炎症性肠病（IBD）。该提议旨在利用 通过 将细菌效应子分子改编为治疗剂。实现治疗潜力的主要挑战 这些分子是能够设计能够在肠内递送蛋白质的输送系统的能力 上皮细胞。该提案的目的是创建具有能力的细菌蛋白纳米颗粒 提供细菌效应蛋白，抑制上皮炎症并减轻IBD的症状。钥匙 结果是：（1）一种新的，长期以来的IBD治疗性，逮捕了源头的炎症； （2）一个新 利用细菌免疫调节机制和工程师的治疗范式 临床生存能力必不可少的输送策略。已经设定了三个具体目标： 目标1。纳米颗粒的细胞摄取和运输特性以最大化蛋白质 送货。细菌蛋白纳米颗粒将以不同的生理学特征制造，包括大小， 交联密度，靶向配体和内体逃生基序。暴露于纳米颗粒的上皮细胞 体外将评估颗粒内在化，内体逃生和分离为可溶性蛋白质的粒子内在化。 AIM 2。评估对细菌蛋白纳米颗粒的体外和EXVIVO生物学反应。各种各样的 纳米颗粒制剂，包括AIM 1的配方以及在此目的中优化的颗粒 通过粘液将应用于非极化和偏振上皮细胞，并进行体内粘膜制剂 在一系列剂量上。功能活性将通过粘膜摄取，抑制免疫来测量 信号通路，炎症细胞因子的水平降低。 AIM 3。确定针对体内递送的蛋白质纳米颗粒的治疗作用 患病的动物。纳米颗粒将通过表面涂层进行修改，以提高其横穿的能力 胃肠道和靶标发炎的粘膜。这些颗粒将用于用诱导的小鼠施用 结肠炎的化学，免疫和遗传模型以及健康对照。临床参数，粘膜 和系统性炎症标记和组织病理学将在相关时间点进行跟踪。

项目成果

Bioengineering Bacterially Derived Immunomodulants: A Therapeutic Approach to Inflammatory Bowel Disease.

• DOI: 10.1021/acsnano.7b03239
• 发表时间: 2017-10-24
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Herrera Estrada L;Wu H;Ling K;Zhang G;Sumagin R;Parkos CA;Jones RM;Champion JA;Neish AS
• 通讯作者: Neish AS