Exploring 15-hydroxyprostaglandin dehydrogenase as a molecular target for treating inflammatory bowel diseases

 描述（由申请方提供）：本提案基于以下假设：抑制15-羟基前列腺素脱氢酶（15-PGDH）将为炎症性肠病（IBD）提供一种新型、安全和有效的治疗方法。炎症性肠病的特点是反复发作的腹痛和出血性腹泻沿着其他表现，在美国估计有110万人受到影响。目前的治疗选择如氨基水杨酸盐、皮质类固醇和抗TNF-α剂与不良反应相关，并且在诱导临床反应方面不完善，20%的溃疡性结肠炎和66%的克罗恩病患者仍然需要手术。因此，需要更有效的疗法。前列腺素E2（PGE 2）维持胃肠道的许多功能，并在粘膜损伤后的细胞增殖中起重要作用。在IBD动物模型中，阻断PGE 2的作用与结肠炎恶化相关;而增加PGE 2信号传导可改善疾病。15-PGDH是负责PGE 2代谢限速步骤的酶。该提案探讨了抑制15-PGDH是增加肠道组织PGE 2水平的优选和有效方法的假设，并将为IBD提供安全有效的治疗。为了探索这种治疗思路，已经鉴定了具有体内稳定性的15-PGDH的新型高亲和力抑制剂SW 033291。在本研究中，该抑制剂将用于研究直接调节IBD小鼠模型中15-PGDH的作用。在本研究中，我们将首先直接确定SW 033291对溃疡性结肠炎小鼠模型中疾病活动的影响。我们的假设是，15-PGDH的抑制将显着改善疾病的严重程度，通过粘膜保护作用介导的影响，增加PGE 2对维持干细胞和增殖细胞在结肠隐窝。为了探究这一提出的机制，将使用干细胞报告小鼠（以检查LGR 5和LRIG 1标记的结肠干细胞）和BrdU掺入（以检查隐窝中的干细胞和转运扩增细胞）评估抑制15-PGDH对不同结肠隐窝细胞群的影响。此外，由于IBD相关的癌症发展不依赖于负责合成胰高血糖素的环加氧酶，我们假设抑制15-PGDH将降低结肠炎相关的结肠癌风险，即，我们假设SW 033291对降低结肠炎疾病活动性和降低癌症风险的作用将占主导地位，在非结肠炎相关癌症模型中，PGE 2的增殖作用与癌症风险相关。总之，这些实验将提供15-PGDH作为治疗IBD的新分子靶点的深入表征，并将为使用15-PGDH抑制剂治疗IBD患者建立坚实的转化基础。这个项目将进一步为我提供坚实的基础和培训，以追求我在学术医学和医学研究方面的个人目标。

 DESCRIPTION (provided by applicant): This proposal is based on the hypothesis that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) will provide a novel, safe, and effective therapy for inflammatory bowel diseases (IBD). Inflammatory bowel diseases are marked by recurrent bouts of abdominal pain and bloody diarrhea along with other manifestations, and affect an estimated 1.1 million people in the United States. Current treatment options such as aminosalicylates, corticosteroids, and anti-TNF-a agents are associated with adverse effects and are imperfect in inducing a clinical response, with surgery still required for 20% of ulcerative colitis and 66% of Crohn's disease patients. Thus, there is a need for more effective therapies. Prostaglandin E2 (PGE2) maintains many functions of the gastrointestinal tract and is important in cellular proliferation after mucosal injury. Blocking th effects of PGE2 is associated with exacerbated colitis in IBD animal models; whereas, increasing PGE2 signaling ameliorates disease. 15-PGDH is the enzyme responsible for the rate-limiting step of PGE2 metabolism. This proposal explores the hypothesis that inhibition of 15-PGDH is a preferred and effective method to increase tissue PGE2 levels in the intestine and will provide a safe and effective therapy for IBD. To explore this treatment idea, a novel high-affinity inhibitor of 15-PGDH, SW033291, with in vivo stability has been identified. In this proposal, this inhibitor will be used to investigate the effects of modulating 15-PGDH directly in mice models of IBD. In this study, we will first directly determine the effects of SW033291 on disease activity in a mouse model of ulcerative colitis. Our hypothesis is that inhibition of 15-PGDH will markedly ameliorate disease severity through a mucosal protective effect mediated by effects of increased PGE2 on maintenance of stem and proliferating cells in the colonic crypts. To interrogate this proposed mechanism, the effects of inhibiting 15-PGDH on distinct colonic crypt cell populations will be assessed using both stem cell reporter mice (to examine LGR5 and LRIG1 marked colonic stem cells) and BrdU incorporation (to examine both stem cells and transit amplifying cells in the crypt). Moreover, as IBD-associated cancer development is independent of cyclooxygenases, the enzymes responsible for synthesizing prostaglandins, we hypothesize that inhibiting 15-PGDH will decrease colitis-associated colon cancer risk, i.e. we hypothesize that the effects of SW033291 on reducing colitis disease activity and lowering cancer risk will dominate the pro- proliferative effects of PGE2 that are associated with cancer risk in models of non-colitis associated cancer. Taken together, these experiments will provide an in-depth characterization of 15-PGDH as a new molecular target for treating IBD and will establish a solid translational foundation for using 15-PGDH inhibitor therapy in treating IBD patients. This project will further provide me a solid foundation and training for pursuing my personal goals of a career in academic medicine and medical research.