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.

生物工程细菌衍生的免疫调节剂：IBD 的一种新治疗方法 项目概要 长期目标是开发利用免疫调节特性的新颖、有效的治疗方法 用于治疗炎症性肠病（IBD）的细菌分子。该提案旨在利用 肠道病原体进化出控制宿主炎症相关信号通路的能力，通过 采用细菌效应分子作为治疗剂。实现治疗潜力的主要挑战 这些分子能够设计出能够在肠道内输送蛋白质的输送系统 上皮细胞。该提案的目标是创建能够 传递细菌效应蛋白、抑制上皮炎症并减轻 IBD 症状。钥匙 结果是：(1) 一种长期需要的新的 IBD 治疗方法，可以从源头抑制炎症； (2)新的 利用细菌免疫调节机制并设计纳米颗粒的治疗范例 交付策略对于临床可行性至关重要。制定了三个具体目标： 目标 1. 设计纳米颗粒的细胞摄取和运输特性，以最大限度地提高蛋白质含量 送货。细菌蛋白纳米粒子将被制造成具有不同的理化特征，包括尺寸、 交联密度、靶向配体和内体逃逸基序。暴露于纳米粒子的上皮细胞 体外将评估颗粒内化、内体逃逸和解离成可溶性蛋白质。 目标 2. 评估对细菌蛋白纳米颗粒的体外和离体生物反应。各种各样的 纳米颗粒配方，包括来自目标 1 的配方以及为此目的优化的颗粒 通过粘液，将应用于非极化和极化上皮细胞，以及离体粘膜制剂 在一定剂量范围内。功能活动将通过粘膜摄取、免疫抑制来测量 信号通路，并降低炎症细胞因子的水平。 目标 3. 确定针对体内递送优化的蛋白质纳米颗粒的治疗效果 患病的动物。纳米颗粒将通过表面涂层进行修饰，以提高其穿过介质的能力。 胃肠道和目标发炎的粘膜。这些颗粒将被施用于诱导小鼠 结肠炎的化学、免疫学和遗传模型以及健康对照。临床参数，粘膜 将在相关时间点跟踪全身炎症标志物和组织病理学。

项目成果

Alginate/chitosan microparticles for gastric passage and intestinal release of therapeutic protein nanoparticles.

海藻酸盐/壳聚糖微粒用于治疗性蛋白质纳米颗粒的胃通过和肠道释放。

• 发表时间: 2019
• 作者: Ling, Kevin;Wu, Huixia;Neish, Andrew S;Champion, Julie A
• 通讯作者: Champion, Julie A

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

生物工程细菌衍生的免疫调节剂：炎症性肠病的治疗方法。

• 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