INTERLEUKIN-6 AND AGING: IMPACT ON IMMUNE DEFENSE AND TISSUE REPAIR IN URINARY BLADDER

 描述（由申请人提供）：60%的妇女将遭受尿路感染（UTI）在某些时候在他们的生活和三分之一的妇女与急性UTI将遭受复发性UTI。这种疾病对于绝经后的妇女尤其成问题，其中超过50%的妇女将具有不能用抗生素治愈的复发性感染。这种增加的易感性可能是由于伴随衰老的雌激素水平降低。然而，这种易感性增加背后的机制尚不清楚，这种知识的缺乏阻碍了我们开发治疗和预防UTI的新策略的能力，特别是在绝经后妇女中。在这里，我们专注于细胞因子，白细胞介素-6（IL-6），这是快速上调在UTI在人类，和多项研究表明，绝经后妇女有升高的血清IL-6水平。最近的研究表明，IL-6信号不仅调节先天免疫反应，而且对于及时的伤口愈合和组织再生也是必不可少的。在初步研究中，我们证明，IL-6的损失损害了宿主对UPEC的反应，老年雌性小鼠表现出高水平的IL-6，增加巨噬细胞的募集，并损害组织修复。我们的目标是确定如何在1）激活先天免疫系统（巨噬细胞）以摧毁病原体（主要是尿路致病性大肠杆菌）之间实现平衡。大肠杆菌[UPEC]）和2）修复膀胱上皮。我们将测试中心假设，即IL-6是宿主防御和上皮细胞稳态之间的平衡的关键调节因子。在目标1中，我们将剖析IL-6信号转导在调节免疫和上皮细胞对UTI的反应中的功能，以及这种蛋白质功能的丧失如何损害宿主的防御反应。在目标2中，我们将确定衰老影响小鼠和女性UTI结果的机制。重要的是，我们将利用我们的机制的见解，以确定是否选择性雌激素受体激动剂或抗IL-6治疗将是有效的治疗。我们预计，我们的工作将提供新的见解之间的分子相互作用的雌激素和膀胱宿主防御在UTI。此外，这些实验将提供一个基础，以确定雌激素和抗IL-6治疗是否将是患有慢性复发性UTI的绝经后妇女的有效干预措施，并将有助于开发针对绝经期妇女的预防性干预措施和治疗。

 DESCRIPTION (provided by applicant): 60% of women will suffer from a urinary tract infection (UTI) at some point in their lives and a third of women with an acute UTI will suffer recurrent UTIs. This disease is especially problematic for post- menopausal women where over 50% will have recurrent infections that cannot be cured with antibiotics. This increased susceptibility is likely due to reduced estrogen levels that accompany aging. However, the mechanisms behind this increased susceptibility are unknown, and this lack of knowledge impedes our ability to develop new strategies for the treatment and prevention of UTIs, especially in post-menopausal women. Here, we focus on the cytokine, interleukin-6 (IL-6), which is rapidly upregulated during UTIs in humans, and multiple studies have shown that postmenopausal women have elevated serum levels of IL-6. Recent studies indicate that IL-6 signaling not only modulates innate immune responses but also is essential for timely wound healing and tissue regeneration. In preliminary studies, we demonstrate that loss of IL-6 impairs the host response to UPEC and that aged female mice exhibit high levels of IL-6, increased recruitment of macrophages, and impaired tissue repair. Our objective here is to determine how balance is achieved between 1) activating the innate immune system (macrophages) to destroy the pathogen (predominantly uropathogenic E. coli [UPEC]) and 2) repairing the bladder epithelium. We will test the central hypothesis that IL-6 is a key regulator of the balance between host defense and epithelial homeostasis. In Aim 1, we will dissect the function of IL-6 signaling in modulating the immune and epithelial response to a UTI and how loss of function of this protein impairs host defense response. In Aim 2, we will determine the mechanisms whereby aging influences UTI outcome in mice and women. Importantly, we will leverage our mechanistic insights to determine whether selective estrogen receptor agonists or anti-IL6 therapies will be effective treatments. We anticipate that our work will provide new insights into the molecular interplay between estrogen and bladder host defense during a UTI. In addition, the experiments will provide a foundation upon which to determine whether estrogen and anti-IL-6 therapies will be effective interventions in post-menopausal women suffering from chronic, recurrent UTIs and will help to develop preventive interventions and treatments that are optimized for menopausal women.