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.

传染病是重大的卫生保健问题。由于该病的发病机制都是由