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Intestinal IL-17RA signaling and mucosal host defense

Intestinal IL-17RA signaling and mucosal host defense
肠道 IL-17RA 信号传导和粘膜宿主防御
批准号:
10605304
负责人:
Pawan Kumar
金额:
$41.3万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-07-01 至 2025-04-30

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中文摘要
翻译
炎症性肠病(IBD),包括溃疡性结肠炎(UC)和克罗恩病(CD),是一种常见的肠道疾病。 这种毁灭性的疾病影响着美国数百万人。潜在的机制导致 对IBD的了解很少。潘氏细胞及其抗菌产物(α-防御素、溶菌酶等)发挥 在小肠宿主防御中起关键作用,它们的失调构成CD的致病因素。CD 患者存在潘氏细胞异常、α-防御素表达减少和IL-17 A水平升高, 发炎的组织IL-17 A/IL-17 F轴是肠道炎症和保护性炎症的已知驱动因素。 在小鼠模型和人IBD中的反应,但关于IL-10的特异性细胞小生境知之甚少。 17 A/F受体信号传导和IL-17 A介导的肠道宿主防御的分子机制。我们 是第一个表明肠道IL-17 A宿主防御反应的消除导致肠道免疫缺陷的人。 小肠中的生态失调和免疫应答失调。尽管有无数的胃肠道 虽然IL-17 A刺激的防御反应,但文献未能阐明IL-17 A刺激的防御反应是否 损伤或感染是直接刺激功能上不同吸收或分泌成熟 上皮细胞类型或它们是否是干细胞衍生的结果。因此,不知道IL-17 A是否 直接或间接调节肠道中潘氏细胞和其他细胞类型的效应子功能。我们发现IL-17 A/F IL-17受体(IL-17 RA/IL-17 RC)在功能上不同的吸收细胞(肠上皮细胞)、分泌细胞 (Paneth)、Lgr 5+肠干细胞(ISC)和肠的转运扩增(TA)祖细胞。 然而,关于IL-17 A是否直接或间接调节潘氏细胞、ISCs 和祖细胞的功能。我们现在有令人信服的证据表明IL-17 A直接调节 在肠的潘氏细胞、ISCs和ATOH 1+祖细胞中具有独特和特异性的功能。ATOH 1是 肠分泌细胞的谱系定型所需的,包括潘氏细胞。去调查血统- 在特定功能中,我们产生并验证了整个肠上皮(Villin-cre)、潘氏细胞(Defa 6-cre)和 Atoh 1特异性(Atoh 1-cre)新型IL-17 RA(Il 17 rafl/fl)条件性敲除小鼠。目标1中的拟议研究 将试图了解IL-17 RA信号转导在调节ISC和Paneth细胞功能中的作用, 稳态条件在目标2中,使用多种肠道炎症模型和我们的谱系特异性IL-10, 17 RA条件性基因敲除小鼠,我们将确定IL-17 A如何调节特异性的独特和新颖的功能。 小肠和大肠中的细胞类型。这些研究将对IBD研究产生直接影响 了解IL-17 RA信号传导小肠和大肠主要细胞类型的新作用。完成 这些研究将提供一个复杂的分子作用机制的理解IL- 17 A调节肠道炎症。
英文摘要
Inflammatory bowel disease (IBD), which comprises Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a devastating disease that impacts millions of people in the United States. The underlying mechanisms leading to IBD are poorly understood. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in small intestinal host defense and their dysregulation constitutes a pathogenic factor for CD. CD patients have Paneth cell abnormalities, reduced expression of a-defensins and elevated levels of IL-17A in the inflamed tissue. The IL-17A/IL-17F axis is a known driver of intestinal inflammatory and protective responses in mouse models and human IBD, but little is known regarding the specific cellular niches of IL- 17A/F receptor signaling and the molecular mechanisms of IL-17A-mediated host defense in the intestines. We were the first to show that the abrogation of intestinal IL-17A host defense responses leads to commensal dysbiosis and dysregulated immune responses in the small intestine. Despite the myriad of gastrointestinal tract responses to IL-17A stimulation, the literature has failed to elucidate whether the defense responses to injury or infection are a result of direct stimulation to functionally distinct absorptive or secretory mature epithelial cell types or if they are stem cell-derived consequences. Therefore, it is not known whether IL-17A directly or indirectly modulates Paneth and other cell types effector function in the gut. We found that IL-17A/F receptor (IL-17RA/IL-17RC) is expressed on functionally distinct absorptive cells (enterocytes), secretory cells (Paneth), Lgr5+ intestinal stem cells (ISCs) and transit-amplifying (TA) progenitor cells of the intestine. However, almost nothing is known regarding whether IL-17A directly or indirectly modulates Paneth cells, ISCs and progenitor cells function. We now have compelling evidence suggesting that IL-17A directly regulates unique and specific functions in Paneth cells, ISCs and ATOH1+ progenitor cells of intestine. ATOH1 is required for lineage commitment of intestinal secretory cells, including Paneth cells. To investigate lineage- specific function, we generated and validated entire gut epithelium (Villin-cre), Paneth cell (Defa6-cre) and Atoh1-specific (Atoh1-cre) novel IL-17RA (Il17rafl/fl) conditional knockout mice. The proposed studies in Aim 1 will seek to understand the role of IL-17RA signaling in regulating ISC and Paneth cell function under homeostatic conditions. In Aim 2, using multiple models of intestinal inflammation and our lineage-specific IL- 17RA conditional knockout mice, we will determine how IL-17A regulates unique and novel functions in specific cell types in the small and large intestine, respectively. These studies will have a direct impact in IBD research to understand the novel role of IL-17RA signaling major cell types of the small and large intestine. Completion of these studies will provide a needed understanding of the complex molecular mechanisms of actions of IL- 17A in regulating intestinal inflammation.
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会议论文
Paneth cell-specific IL-22Ra1 signaling in mucosal host defense
Investigating the role of Akkermansia muciniphila and intestinal IL-17RA signaling in autoimmune inflammation
Intestinal IL-17RA signaling and mucosal host defense
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