VITAMIN D COMPOUNDS FOR INFLAMMATORY BOWEL DISEASE

克罗恩病（CD）和溃疡性结肠炎（UC）是炎症性肠病 (IBD)病因不明，特征为慢性胃肠道（GI） 炎症IBD的关键病理机制可能涉及一种失调的 对胃肠道抗原或感染的免疫应答。炎症性Th 1应答 以干扰素-γ和肿瘤坏死因子-α合成为特征 与IBD相关，而Th 2应答特征为白细胞介素-4 和转化生长因子β-1的合成与保护 IBD的。易感基因有助于IBD，但遗传这些基因是 不足以发展疾病。未定义的环境风险因素 发挥着决定疾病的作用。 我们假设， 维生素D生物合成是IBD的环境危险因素。我们建议 使用具有生物活性的维生素D代谢物1，25-二羟基维生素D3， 抑制IBD发展和治疗IBD鼠模型中已建立IBD 作为开发新的治疗策略的第一步， 疾病 拟定商业应用： 不可治愈的IBD折磨着200万人，每年花费约12亿美元 治疗。类固醇，免疫抑制剂和IBD的手术治疗 症状有不希望的副作用。FDA批准的短期 治疗（小鼠-人抗肿瘤坏死因子IgG 1单克隆抗体- alpha）预计年销售额为1亿美元。的商业潜力 一种长期的基于维生素D的治疗可能超过1亿至1.5亿美元。

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown etiology characterized by chronic gastrointestinal (GI) tract inflammation. The key pathological mechanism in IBD may involve a dysregulated immune response to GI tract antigens or infections. Inflammatory Th1 responses characterized by interferon-gamma and tumor necrosis factor-alpha synthesis correlate with IBD, whereas Th2 responses characterized by interleukin-4 and transforming growth factor beta-1 synthesis correlate with protection from IBD. Susceptibility genes contribute to IBD, but inheriting these genes is not sufficient for disease development. Undefined environmental risk factors play a disease-determining role. We hypothesize that insufficient sunlight for vitamin D biosynthesis is an environmental risk factor for IBD. We propose to use the hormonally active vitamin D metabolite, 1,25-dihydroxy vitamin D3 to inhibit IBD development and to treat established IBD in murine models of IBD as a first step in developing a novel therapeutic strategy for this incurable disease. PROPOSED COMMERCIAL APPLICATION: Incurable IBD afflicts two million individuals and costs about $1.2 billion annually to treat. The steroids, immunosuppressants and surgical treatments for IBD symptoms have undesireable side-effects. An FDA-approved short-term treatment (mouse-human IgG1 monoclonal antibody to tumor necrosis factors- alpha) has projected annual sales of $100 million. The commercial potential of a long-term vitamin D-based therapeutic might be greater than $100-150 million.