The impact of dysbiosis and the IL-12/23 signaling axis on IBD-associated bone loss.

生态失调和 IL-12/23 信号轴对 IBD 相关骨质流失的影响。

• 批准号: 10320025
• 负责人: Christopher Thomas Peek
• 金额: $ 5.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320025
• 关键词: Adaptor Signaling Protein; Affect; Antibodies; Bacterial DNA; Bacterial Translocation; Biology; Bone Resorption; Bone remodeling; Cell Lineage; Cell physiology; Cells; Childhood; Chronic; Citrobacter rodentium; Clinical; Clinical Trials; Coculture Techniques; Colitis; Data; Disease model; Effector Cell; Equilibrium; Etiology; Exhibits; Femur; Fracture; Funding; Future; Gastrointestinal Diseases; General Population; Genetic; Glucocorticoids; Goals; Homeostasis; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-12; Intestinal Diseases; Intestines; Kinetics; Knock-out; Knockout Mice; Ligands; Malnutrition; Measures; Membrane; Mentorship; Modeling; Molecular; Mus; NF-kappa B; Nutritional; Osteoblasts; Osteoclasts; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Pattern recognition receptor; Physicians; Positioning Attribute; Production; Research Proposals; Risk; Role; Scientist; Serology; Signal Transduction; Sodium Dextran Sulfate; Symptoms; TNF gene; Testing; Therapeutic; Training; Tumor necrosis factor receptor 11b; United States National Institutes of Health; bone; bone cell; bone loss; career; chemically induced colitis; cytokine; design; dysbiosis; epithelial injury; experience; experimental study; gastrointestinal; gastrointestinal epithelium; gut microbiome; gut microbiota; improved; in vitro Assay; in vivo; interest; interleukin-23; microbial; microbiome; microbiota; morphogens; murine colitis; osteoclastogenesis; osteoporosis with pathological fracture; pathogen; pathogenic microbe; receptor; skeletal; skeletal abnormality; systemic inflammatory response

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) is characterized by severe gastrointestinal inflammation and changes in the intestinal microbiota. Many IBD patients also experience extra-intestinal manifestations. Skeletal abnormalities are a frequent extra-intestinal manifestation of IBD, and patients exhibit up to a 40% increased risk of incurring fractures compared to the general population. Although many factors, including malabsorptive malnutrition and glucocorticoid use, contribute to IBD-associated bone loss, nutritionally replete and glucocorticoid naive patients remain susceptible to bone loss. While changes in both the intestinal microbiome and inflammatory cytokines occur in IBD, the precise mechanisms of IBD-associated bone loss are unclear. We have therefore established complementary mouse models of colitis-driven bone loss, and are uniquely positioned to use skeletal specific genetic knockout mice to define inflammatory and microbiotic drivers of IBD-associated bone loss. My preliminary data implicate the IL-12/23 signaling axis in the pathogenesis of bone loss during colitis. Intriguingly, these cytokines share a common subunit, IL-12/23p40 (p40), yet exert opposing effects on bone remodeling. IL-12 inhibits osteoclast differentiation, while IL-23 leads to bone resorption through enhanced osteoclastogenesis. Dual blockade of IL-12/23 is used clinically via monoclonal p40 antibodies; however, the effect of p40 blockade on bone remodeling during gastrointestinal inflammation is unclear. In addition to the impact of cytokines on skeletal homeostasis, emerging evidence has identified the intestinal microbiome as a regulator of bone remodeling. Many studies have characterized changes in the IBD intestinal microbiome and demonstrated that these changes are transmitted systemically by crossing the gut epithelium. Importantly, skeletal cells sense and respond to microbial components through pattern recognition receptors, many of which are dependent on the adaptor protein, MyD88. The overarching hypothesis of this proposal is that 1) IL-12/23 signaling and 2) circulating microbial components impact skeletal homeostasis during gastrointestinal inflammation. I will test this hypothesis with two complementary Specific Aims. In Specific Aim 1, I will define the role of IL-12/23 signaling on direct and indirect osteoclastogenesis during colitis. In Specific Aim 2, I will determine the impact of skeletal MyD88-dependent PRRs on colitis-associated bone loss. Successful completion of the proposed experiments will elucidate fundamental mechanisms by which systemic cytokines and circulating microbiota components impact bone biology during colitis and provide a platform to test the role of alternative colitis-associated cytokines in pathologic bone loss. Furthermore, these studies will clarify how therapeutic IL- 12 and IL-23 dual blockade in patients with IBD impacts skeletal homeostasis. Collectively, this proposal will investigate how the IL-12/23 signaling axis and the microbiome impact skeletal homeostasis during gastrointestinal inflammation while providing the ideal training and mentorship to develop my future career as an independent, NIH-funded pediatric physician-scientist.

项目总结/摘要 炎症性肠病（IBD）的特征在于严重的胃肠道炎症和肠道炎症的改变。 肠道微生物群许多IBD患者还经历肠外表现。骨骼异常 是IBD的常见肠外表现，患者表现出高达40%的风险增加， 与普通人群相比，尽管许多因素，包括吸收不良营养不良和 糖皮质激素的使用，导致IBD相关的骨丢失，营养充足和糖皮质激素初治患者 仍然容易骨质流失。虽然肠道微生物组和炎症的变化 尽管IBD中存在细胞因子，但IBD相关骨丢失的确切机制尚不清楚。我们有 因此，建立了结肠炎驱动的骨丢失的互补小鼠模型，并且独特地定位于 使用骨骼特异性基因敲除小鼠来定义IBD相关的炎症和微生物驱动因素 骨质流失我的初步数据暗示IL-12/23信号轴在骨丢失的发病机制中， 结肠炎有趣的是，这些细胞因子共享一个共同的亚基，IL-12/23 p40（p40），但对IL-12/23 p40发挥相反的作用。 骨重建IL-12抑制破骨细胞分化，而IL-23通过增强骨吸收而导致骨吸收。 破骨细胞生成IL-12/23的双重阻断在临床上通过单克隆p40抗体使用;然而， 在胃肠道炎症期间，p40阻断对骨重建的影响尚不清楚。除了有 细胞因子对骨骼动态平衡的影响，新的证据已经确定肠道微生物组是一个 骨重建的调节器。许多研究已经表征了IBD肠道微生物组的变化， 表明这些变化是通过穿过肠道上皮系统性传播的。重要的是， 骨骼细胞通过模式识别受体感知和响应微生物成分，其中许多 依赖于衔接蛋白MyD 88。该提议的总体假设是：1）IL-12/23 信号传导和2）循环微生物组分影响胃肠期间的骨骼稳态 炎症我将用两个互补的具体目标来检验这个假设。在具体目标1中，我将定义 IL-12/23信号在结肠炎期间直接和间接破骨细胞生成中的作用。在第二个目标中，我将 确定骨骼MyD 88依赖性PRR对结肠炎相关骨丢失的影响。成功完成 的拟议实验将阐明的基本机制，全身细胞因子和循环 微生物群成分影响结肠炎期间的骨生物学，并提供了一个平台来测试替代疗法的作用。 结肠炎相关细胞因子在病理性骨丢失中的作用此外，这些研究将阐明治疗性IL- IBD患者中IL-12和IL-23双重阻断影响骨骼稳态。总的来说，这项建议将 研究IL-12/23信号轴和微生物组如何影响骨骼稳态， 胃肠道炎症，同时提供理想的培训和指导，以发展我未来的职业生涯， 独立的，NIH资助的儿科医生兼科学家。