Methods to modulate GI inflammatory and infectious diseases

调节胃肠道炎症和传染病的方法

• 批准号: 10867133
• 负责人: Hyunjoon Kim
• 金额: $ 21.21万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10867133
• 关键词: Adjuvant; Animal Model; Antibiotics; Antigens; Attenuated; B-Cell Activation; Bacteria; Biodistribution; Biological Assay; Biology; Cell Line; Cells; Chemicals; Chronic; Communicable Diseases; Dendritic Cells; Disease; Drug Delivery Systems; Drug Kinetics; Encapsulated; Endothelial Cells; Flow Cytometry; Gastrointestinal tract structure; Goals; Healthcare; Histologic; Immune; Immunity; Immunoglobulin A; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Intestines; Libraries; Measures; Methods; Mucosal Immunity; Mutate; Oral; Organ; Pathogenesis; Pharmaceutical Preparations; Regimen; Rodent; Route; Safety; Small Intestines; Source; System; T-Lymphocyte; TNF gene; Therapeutic; Vaccine Adjuvant; Vaccines; Virus; cytokine; efficacy validation; fluorescence imaging; gastrointestinal; high throughput screening; high-throughput drug screening; in vitro Assay; in vivo; liquid chromatography mass spectrometry; mesenteric lymph node; nano; nanoparticle; nanoparticle drug; nanoparticulate; nanopolymer; nanotoxicity; novel; pathogen; prophylactic; screening; small molecule; standard of care; uptake; vaccine development

Infectious diseases are significant healthcare problems. As pathogenesis of the disease are triggered by bacteria and virus, commonly used medications are small molecule drugs. However, bacteria and virus often mutate and makes it challenging to develop a standard of care medications. Hence, vaccines, which are immunotherapy regimens to inject live or attenuated antigens to develop immunity against the pathogens are used for prophylactic and therapeutic applications. However, vaccines are less effective against gastrointestinal (GI) infectious diseases as generating mucosal immunity requires extensive activation of GI immune cells. In this study, we aim to develop a vaccine adjuvant system which can be delivered by oral route, and selectively activate GI immune cells to elicit strong mucosal immunity which will be pursued by following specific aims. Aim1. We will identify a novel small molecule which can specifically activate GI immune cells without triggering chronic GI inflammation. To do so, we will develop in vitro assays which allow high throughput screen (HTS) of drug libraries. Using HTS assay, we will discover a hit compound that induces pro-inflammatory cytokine, TNF-alpha from primary dendritic cells but does not induce TNF-alpha from GI endothelial cell line Caco-2. Then, we will develop a nanoparticle drug delivery carrier suitable for oral delivery. We will develop polymeric nanoparticles that can provide protection of the hit compound from degradation in the GI tract, and enhance uptake by GI immune cells in the intestine, all of which are important for inducing mucosal immunity in GI tract. Aim 2. Hit compound encapsulating nanoparticles (refer to as Nano-Adjuvant) will be examined for in vivo safety and efficacy in rodent animal models. Biodistribution and pharmacokinetic profile of nanoparticles will be measured using IVIS fluorescence imaging and LC/MS analysis and histological analysis of organs will be performed to investigate the potential toxicity of Nano-adjuvant. Next, we will examine the immunostimulatory efficacy of Nano-adjuvant by measuring the T cell and B cell activation (small intestinal cells, mesenteric lymph nodes) using flow cytometry, and mucosal immunity (Intestinal wash IgA, fecal IgA). In this proposal, we will focus our efforts to examine whether oral nanoparticulate delivery of small molecule can elicit strong mucosal immunity without inducing GI inflammation by HTS screening and in vivo safety and efficacy validations. Long term goal of the project is to develop a universal oral immunostimulatory adjuvant which can be used as a vaccine when combined with antigen sources, or as a complementary immunotherapy agent when combined with anti-biotics or anti-virus drugs to treat GI infectious diseases.

传染病是重大的医疗问题。由于疾病的发病机理是由 细菌和病毒，常用药物是小分子药物。但是，细菌和病毒经常 突变并使制定护理标准药物的挑战。因此，疫苗是 免疫疗法方案以对病原体产生免疫力注射活性或减弱的抗原是 用于预防性和治疗应用。但是，疫苗对胃肠道有效性较低 （GI）传染病作为产生粘膜免疫需要广泛激活GI免疫细胞。在这个 研究，我们旨在开发一种可以通过口头途径传递的疫苗辅助系统，并有选择地 激活胃肠道免疫细胞以引起强烈的粘膜免疫，这将通过以下特定目的来追求。 AIM1。我们将确定一个新型的小分子，该分子可以特异性地激活GI免疫细胞而无需 触发慢性胃肠道炎症。为此，我们将开发体外测定，以允许高通量屏幕 （HTS）毒品库。使用HTS测定法，我们将发现一种诱导促炎性的热门化合物 细胞因子，TNF-α来自原代树突状细胞，但不会诱导GI内皮细胞系的TNF-α Caco-2。然后，我们将开发适合口服输送的纳米颗粒药物输送载体。我们将发展 可以保护命中化合物免受胃肠道降解的聚合物纳米颗粒，并且 加强肠道中GI免疫细胞在肠中的摄取，所有这些都对诱导粘膜免疫很重要 胃肠道。 AIM 2。将检查纳米颗粒（指纳米甲状腺） 啮齿动物模型的安全性和功效。纳米颗粒的生物分布和药代动力学特征将是 使用IVIS荧光成像和LC/MS分析以及对器官的组织学分析测量的将是 进行研究以研究纳米辅助的潜在毒性。接下来，我们将检查免疫刺激性 通过测量T细胞和B细胞激活（小肠细胞，肠系膜淋巴），纳米辅助的功效 节点）使用流式细胞仪和粘膜免疫（肠道WASH IGA，粪便IGA）。 在此提案中，我们将集中精力检查口服纳米核心是否递送小分子 可以通过HTS筛查和体内安全性引起GI炎症而引起强烈的粘膜免疫力 功效验证。该项目的长期目标是开发通用的口服免疫刺激性佐剂 与抗原源混合或互补免疫疗法时，可以用作疫苗 当与抗生素或抗病毒药物结合使用以治疗胃肠道传染病时。