Role of Lipocalin 2 Inflammatory Bowel Disease

脂质运载蛋白 2 在炎症性肠病中的作用

• 批准号: 8577770
• 负责人: MATAM VIJAY-KUMAR
• 金额: $ 29.9万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577770
• 关键词: Acute; Acute-Phase Proteins; Adhesions; Affect; Affinity; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Award; Bacteria; Binding; Biological; Bone Marrow; Chimera organism; Chronic; Colitis; Coupled; Crohn' s disease; Development; Diet; Dietary Iron; Disease; Europe; Event; Gelatinase A; Generations; Genotype; Goals; Homeostasis; Human; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Iron; Iron Chelation; Knock-out; Knowledge; Measures; Mediating; Mentored Research Scientist Development Award; Mus; Orthologous Gene; Pathogenesis; Play; Post-Translational Protein Processing; Proteins; Reagent; Regulation; Research; Role; Sepsis; Severities; Siderophores; Structure; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Transgenic Organisms; Ulcerative Colitis; clinical application; cytokine; feeding; gut microbiota; insight; neutrophil; novel therapeutics; overexpression; prevent; public health relevance; pyrosequencing; repaired

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is the collective term for chronic idiopathic inflammatory diseases of the intestine, most notably Crohn's Disease (CD) and Ulcerative Colitis (UC), which together affect 1.4 million people in the US and 2.2 million people in Europe. IBD is associated with elevated levels of a number of acute phase proteins (APP) that drive or dampen the inflammatory response. Exploration of the biologic activities of APP has resulted in the development of targeted biological therapeutic agents. Indeed, agents that directly antagonize pro-inflammatory mediators or mimic anti-inflammatory molecules are currently being used and/or developed to treat IBD. However, the biologic activity, and thus therapeutic potential, of some of the most dynamically regulated APP remain unexplored. For example, while levels of the APP lipocalin-2 (Lcn2) increase by several log orders of magnitude in various inflammatory conditions, including murine colitis and human IBD, the extent to which Lcn2 drives or dampens gut inflammation remains unexplored. In addition to its elevated expression being associated with colitis, the multifaceted biologic activity of Lcn2 (as well as that of its human ortholog, Neutrophil Gelatinase-Associated Lipocalin) or NGAL suggests it may play a central role in IBD. Specifically, Lcn2 exerts potent antibacterial activity mediated by sequestering bacterial siderophores and thereby preventing bacteria from scavenging iron from lower affinity host proteins. In addition, Lcn2 participates in iron transport stabilizing highly reactive catalytic iron by chelation. Accordingly, it has been shown that Lcn2 deficient mice are highly susceptible to bacterial and LPS-induced sepsis. We hypothesize that Lcn2's control over iron homeostasis is not limited to the extreme events such as sepsis but, rather, that the dynamic regulation of Lcn2 from low-grade inflammation to acute and chronic colitis plays an important role in preserving gut neutrophil function as well as iron/microbiota homeostasis. Consequently, the goal of this proposal is to investigate the role and mechanism of action of Lcn2 in intestinal inflammation. Establishing the role of this dynamically regulated protein will advance our knowledge of pathogenesis and perhaps allow development of novel therapeutic strategies to treat human IBD. We anticipate that these studies will demonstrate a key role for Lcn2 in protecting the gut. Given its small size, simple structure and biologic activiy in the absence of post-translational modification, Lcn2 may be exploitable as a treatment for intestinal inflammation.

描述（由申请人提供）：炎症性肠病（IBD）是肠道慢性特发性炎症性疾病的统称，最值得注意的是克罗恩病（CD）和溃疡性结肠炎（UC），这两种疾病共影响美国140万人和欧洲220万人。IBD与许多驱动或抑制炎症反应的急性期蛋白（APP）水平升高相关。对APP生物活性的探索导致了靶向生物治疗剂的开发。实际上，目前正在使用和/或开发直接拮抗促炎介质或模拟抗炎分子的药剂来治疗IBD。然而，一些最动态调节的APP的生物活性以及因此的治疗潜力仍然未被探索。例如，虽然APP脂质运载蛋白-2（Lcn 2）的水平在各种炎性病症（包括鼠结肠炎和人IBD）中增加了几个对数数量级，但Lcn 2驱动或抑制肠道炎症的程度仍然未被探索。除了其表达升高与结肠炎相关之外，Lcn 2（以及其人类直系同源物，神经胶质酶相关脂质运载蛋白）或NGAL的多方面生物活性表明其可能在IBD中发挥核心作用。具体而言，Lcn 2发挥有效的抗菌活性 介导的螯合细菌铁载体，从而防止细菌从低亲和力宿主蛋白中清除铁。此外，Lcn 2通过螯合作用参与铁转运稳定高活性催化铁。因此，已经显示Lcn 2缺陷型小鼠对细菌和LPS诱导的脓毒症高度易感。我们假设Lcn 2对铁稳态的控制并不限于极端事件，如脓毒症，而是Lcn 2从低度炎症到急性和慢性结肠炎的动态调节在保护肠道中性粒细胞功能以及铁/微生物群稳态方面起着重要作用。因此，本提案的目标是研究Lcn 2在肠道炎症中的作用和作用机制。确定这种动态调节蛋白的作用将促进我们对发病机制的了解，并可能允许开发新的治疗策略来治疗人类IBD。我们预计这些研究将证明Lcn 2在保护肠道方面的关键作用。鉴于其小尺寸、简单结构和在不存在翻译后修饰的情况下的生物活性，Lcn 2可被开发作为肠道炎症的治疗。