Role of Leptin in murine modeles of IBD

瘦素在 IBD 小鼠模型中的作用

• 批准号: 6727999
• 负责人: Giamila Fantuzzi
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727999
• 关键词: Crohn's disease; SCID mouse; T lymphocyte; dextrans; disease /disorder model; gastrointestinal epithelium; gene targeting; genetically modified animals; hematopoietic stem cells; hormone receptor; hormone regulation /control mechanism; immunocytochemistry; immunoregulation; inflammatory bowel diseases; interleukin 10; laboratory mouse; leptin; neurons; nitrobenzene; receptor expression; ulcerative colitis

DESCRIPTION (provided by applicant): The goal of this project is to investigate the mechanisms by which leptin deficiency regulates susceptibility to intestinal inflammation in mice. In addition to act as a regulator of food intake and energy expenditure, leptin also modulates the immune and inflammatory response. Preliminary data indicate that leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice are resistant to colitis induced by chronic administration of DSS or TNBS. The current application will attempt to identify the cell populations responsible for the observed effects. In Specific Aim 1, to evaluate the relative role played by neuronal leptin receptors (Ob-R) in regulation of intestinal inflammation. DSS and TNBS will be administered to mice with a selective deficiency of Ob-R in neurons and their response compared with that of WF mice. To analyze in more detail the role of hypothalamic Ob-R, DSS- and TNBS-induced intestinal inflammation will be studied in mice in which Ob-R have been specifically deleted in the arcuate and ventromedial nuclei of the hypothalamus by injecting a vector expressing cre recombinase into Ob-Rflox/flox mice. Because the effects of leptin on both bone marrow- and non-bone marrow-derived cells could contribute to modulation of colitis in the models of DSS and TNBS administration, in Specific Aim 2 the relative contribution of Ob-R expression in these two cell populations will be investigated using bone marrow chimeras for Ob-R. WT bone marrow will be transplanted into db/db mice, while WT mice will receive db/db bone marrow and colitis development will be studied. Furthermore, the direct effects of leptin on T lymphocytes . Preliminary data indicate that Ob-R expression on donor T lymphocytes regulates induction of colitis in the model of CD4+ CD45RBhigh cells transfer into SCID mice. The transfer model will be employed in the attempt to dissect the relative role played by Ob-R expression in donor T lymphocytes versus cells in the recipient mouse. To investigate the direct role of Ob-R expression in T lymphocytes in the modulation of colitis induced by DSS or TNBS, mice with a selective deletion of Ob-R in T lymphocytes will be employed. Finally, in Specific Aim 3 production of leptin by immune cells at the site of intestinal inflammation will be evaluated in murine models and in biopsies of patients with IBD. The possible participation of immune-derived leptin in the local inflammatory network will also be investigated.

描述（由申请人提供）：该项目的目标是研究瘦素缺乏调节小鼠肠道炎症易感性的机制。除了充当食物摄入和能量消耗的调节剂之外，瘦素还调节免疫和炎症反应。初步数据表明，瘦素缺陷（ob/ob）和瘦素受体缺陷（db/db）小鼠对长期施用 DSS 或 TNBS 诱导的结肠炎具有抵抗力。当前的应用程序将尝试识别导致观察到的效应的细胞群。在具体目标 1 中，评估神经元瘦素受体 (Ob-R) 在调节肠道炎症中所发挥的相对作用。将 DSS 和 TNBS 给予神经元选择性 Ob-R 缺陷的小鼠，并将其反应与 WF 小鼠进行比较。为了更详细地分析下丘脑 Ob-R 的作用，将在小鼠中研究 DSS 和 TNBS 诱导的肠道炎症，其中通过注射表达 cre 的载体，在下丘脑的弓状核和腹内侧核中特异性删除 Ob-R。将酶重组入 Ob-Rflox/flox 小鼠中。由于瘦素对骨髓和非骨髓源性细胞的影响可能有助于 DSS 和 TNBS 给药模型中结肠炎的调节，因此在特定目标 2 中，Ob-R 表达在这两个细胞群中的相对贡献将使用 Ob-R 的骨髓嵌合体进行研究。 WT骨髓将被移植到db/db小鼠中，而WT小鼠将接受db/db骨髓并研究结肠炎的发展。此外，瘦素对T淋巴细胞有直接影响。初步数据表明，在 CD4+ CD45RBhigh 细胞转移至 SCID 小鼠模型中，供体 T 淋巴细胞上的 Ob-R 表达可调节结肠炎的诱导。该转移模型将用于尝试剖析 Ob-R 表达在供体 T 淋巴细胞与受体小鼠细胞中所起的相对作用。为了研究T淋巴细胞中Ob-R表达在调节DSS或TNBS诱导的结肠炎中的直接作用，将使用T淋巴细胞中选择性删除Ob-R的小鼠。最后，在特定目标 3 中，将在小鼠模型和 IBD 患者的活检中评估肠道炎症部位免疫细胞产生瘦素的情况。免疫源性瘦素在局部炎症网络中的可能参与也将被研究。