Role of Lipocalin 2 Inflammatory Bowel Disease

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，最著名的是克罗恩病（CD）和溃疡性结肠炎（UC），这两种疾病共同影响着美国的 140 万人和欧洲的 220 万人。 IBD 与多种急性期蛋白 (APP) 水平升高有关，这些蛋白可驱动或抑制炎症反应。对 APP 生物活性的探索导致了靶向生物治疗剂的开发。事实上，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 的生物活性和治疗潜力仍未得到探索。例如，虽然 APP lipocalin-2 (Lcn2) 的水平在各种炎症条件下增加几个对数数量级，包括小鼠结肠炎和人类 IBD，但 Lcn2 驱动或抑制肠道炎症的程度仍未被探索。除了与结肠炎相关的表达升高之外，Lcn2（及其人类直系同源物中性粒细胞明胶酶相关脂质运载蛋白）或 NGAL 的多方面生物活性表明它可能在 IBD 中发挥核心作用。具体来说，Lcn2 具有强大的抗菌活性 通过隔离细菌铁载体介导，从而防止细菌从亲和力较低的宿主蛋白中清除铁。此外，Lcn2 参与铁运输，通过螯合稳定高活性催化铁。因此，已经表明 Lcn2 缺陷小鼠对细菌和 LPS 诱导的败血症高度敏感。我们假设Lcn2对铁稳态的控制不仅限于败血症等极端事件，而是Lcn2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/微生物群稳态中发挥着重要作用。因此，本提案的目的是研究 Lcn2 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增进我们对发病机制的了解，并可能有助于开发治疗人类 IBD 的新治疗策略。我们预计这些研究将证明 Lcn2 在保护肠道方面的关键作用。鉴于其尺寸小、结构简单且在没有翻译后修饰的情况下具有生物活性，Lcn2 可能可用于治疗肠道炎症。

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.