Crohn's disease is an inflammatory disorder of the gastrointestinal (GI) tract, likely associated with a hyperactive immune response to commensal bacteria and mucosal damage. The treatments for Crohn's disease and inflammatory bowel diseases (IBDs) in general have the potential for serious side effects. New approaches for controlling the progression of these diseases are needed. A treatment that works at the mucosal surface, to modulate mucosal inflammation and associated GI damage to prevent or reduce disease severity, would change the quality of life for millions worldwide. A recently developed polysaccharide derivative (PAAG) acts at the mucosal surfaces to facilitate a reduction of inflammation and enhanced barrier function by reducing GI damage. Understanding how PAAG directly modulates key mediators in innate host defense and mucosal integrity, such as toll-like receptors (TLR's) and similar pathways is essential in providing a well-tolerated treatment alternative. In vitro cell based assays will assess the influence of PAAG on TLR activation by pathogen associated molecular patterns (PAMP's) and damage associated molecular patterns (DAMP's) in human GI cells via colorometric signal transduction reporter-gene based assays and pathways, focused qPCR analysis. The effectiveness of oral PAAG treatment in the adoptive transfer model of chronic colitis in vivo will be assessed and compared to confirm prior study success in acute GI inflammatory animal models. Genes influencing the therapeutic response of PAAG in the mouse colon, compared to vehicle control will be identified following hypotheses driven gene expression analysis guided by prior gene expression analysis in related models of GI inflammation. Fecal and serum markers, indicative of the level of GI damage and inflammation, will be measured via ELISA and further validate the effectiveness of PAAG treatment. Molecular methods will determine if microbiome diversity is influenced by treatment with PAAG. The goal of this study is to optimize PAAG dosage and elucidate specific mechanisms that facilitate efficacious disease treatment. Successful outcomes will guide further development of this product toward clinical trials of a safe and effective treatment for Crohn's disease and related IBD's.
Public Health Relevance Statement: Public Health Relevance: Crohn's disease is a specific form of debilitating inflammatory bowel disease (IBD) caused by a dysregulated intestinal immune response, associated with a breakdown in the intestinal mucosal barrier and homeostasis. An estimated 1.4 million people in the US suffer from Crohn's disease and a related disease of the colon, ulcerative colitis. Many currently available therapies have significant side effects and little chance of a cure. The development of a novel treatment (PAAG) by Synedgen is expected to treat Crohn's disease and related IBD's by working directly at the mucosal surface to modulate dysregulated inflammation and enhance barrier function, with the potential to improve the quality of life for millions of people worldwide.
NIH Spending Category: Autoimmune Disease; Biotechnology; Crohn's Disease; Dental/Oral and Craniofacial Disease; Digestive Diseases; Genetics; Inflammatory Bowel Disease; Nutrition
Project Terms: Acute; Adoptive Transfer; Adverse effects; Affect; alternative treatment; Animal Model; arm; base; Biological Assay; Cell Line; Cells; Charge; Chemicals; Chronic; clinical toxicology; Clinical Trials; Colitis; Collection; Colon; commensal microbes; Crohn's disease; cytokine; Data; Defensins; Development; Development Plans; Disease; Disease Progression; dosage; Dose; Edema; effective therapy; Effectiveness; Enterococcus; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Escherichia coli; Family; Feces; gastrointestinal; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Cluster; Gene Expression; Gene Expression Profiling; Genes; Goals; Growth; Growth Factor Gene; gut microbiome; Hamsters; Haptoglobins; Histology; HMGB1 gene; Homeostasis; Host Defense; Human; Immune; Immune response; Immune system; improved; In Vitro; in vitro Model; in vivo; Inflammation; Inflammatory; Inflammatory Bowel Diseases; inflammatory marker; inflammatory modulation; Inflammatory Response; Injury; Intestines; Ionizing radiation; Length; Leukocyte L1 Antigen Complex; Malnutrition; Measures; Mediator of activation protein; Methods; microbiome; mimetics; Modeling; Molecular; mouse model; Mucositis; Mucous Membrane; Mus; Necrosis; NF-kappa B; novel; novel strategies; novel therapeutics; nutritional supplementation; Operative Surgical Procedures; Oral; oral mucositis; Outcome; pathogen; Pathway interactions; Pattern; Pattern recognition receptor; Pharmaceutical Preparations; Phase; phase 2 study; Plasma; Polysaccharides; Population; pre-clinical; prevent; Proctitis; product development; Proteins; public health relevance; Quality of life; Radiation; Radiation Syndromes; receptor; Receptor Activation; Receptor Signaling; repaired; Reporter Genes; Research; response; Sampling; Serum Markers; Severity of illness; Signal Pathway; Signal Transduction; standard of care; success; Surface; Symptoms; Therapeutic; Tissues; TLR2 gene; TLR4 gene; Toll-like receptors; Treatment Protocols; treatment response; Ulcer; Ulcerative Colitis; Weight; Work
