FGF23 and the regulation of vitamin D-induced immunity in CKD

FGF23 和维生素 D 诱导的 CKD 免疫调节

• 批准号: 8469859
• 负责人: Martin HEWISON
• 金额: $ 18.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469859
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Address; Adult; Adverse effects; Anti-Bacterial Agents; Antibacterial Response; Cause of Death; Cells; Cessation of life; Childhood; Chronic Kidney Failure; Clinical; Collaborations; Dialysis patients; Dialysis procedure; Endocrine; Endocrine system; Fibroblast Growth Factor Receptors; Functional disorder; Future; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunology; In Vitro; Individual; Infection; Kidney; Kidney Failure; Light; Link; Metabolism; Minerals; Modeling; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Nephrology; Orthopedic Surgery procedures; Patients; Peripheral; Peritoneal; Peritoneal Dialysis; Peritonitis; Physiological; Population; Prevention strategy; Production; Proteins; Regulation; Renal function; Reporting; Research; Risk; Risk Factors; Role; Serum; Signal Transduction; Site; Staging; System; Testing; Therapeutic; Tissues; Vitamin D; antimicrobial; base; bone; cathelicidin; effective therapy; experience; fibroblast growth factor 23; high risk; immune function; inhibitor/antagonist; innovation; inorganic phosphate; interest; killings; monocyte; mortality; novel; novel therapeutics; peer; peripheral blood; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a debilitating health problem with a high rate of mortality. Early stages of CKD are characterized by elevated circulating levels of fibroblast growth factor 23 (FGF23), a key endocrine regulator of phosphate homeostasis and vitamin D metabolism. Elevated FGF23 is an independent risk factor for mortality in CKD patients and individuals with normal renal function but the underlying physiological mechanism for this is unclear. FGF23 is known to suppress renal synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) but its effects on other peripheral tissues have yet to be defined. In preliminary studies in vitro we have shown that FGF23 suppresses synthesis of 1,25(OH)2D by human monocytes, suggesting an entirely novel link between the endocrine and immune systems. We hypothesize that elevated levels of FGF23 in CKD patients act to suppress antibacterial innate immune responses by inhibiting the vitamin D-activation system in monocytes. Local synthesis of 1,25(OH)2D is known to stimulate production of antibacterial proteins such as cathelicidin (LL37), and this may be a pivotal mechanism by which humans respond to infection. Thus for CKD patients who are already vitamin D-insufficient, the exposure of immune cells to high levels of FGF23 will provide an additional impediment to adequate protection against infection. The proposed project will characterize the relationship between vitamin D and FGF23 as positive and negative regulators of human immunity. Planned experiments will determine whether the suppressive effects of FGF23 can be abrogated by active 1,25(OH)2D or its precursor 25-hydroxyvitamin D (25OHD). In this way the proposal will assess potential therapeutic strategies for maintaining optimal immune function in CKD patients. Further innovation in the project will be provided by the use of both peripheral blood and peritoneal monocytes. By using the latter we will aim to define the role of vitamin D as an activator of human antibacterial function at a tissue site where there is high risk of infection. Collectively these studies will seek to identify an entirely novel function for FGF23 at the interface between endocrine and immune function. In doing so, the project will help to shed light on a key mechanism that may explain the pathological impact of FGF23 in CKD and the unchanged high mortality rate in adult and pediatric dialysis patients.

描述（由申请人提供）：慢性肾脏疾病（CKD）是一种使人衰弱的健康问题，死亡率高。CKD的早期阶段的特征在于成纤维细胞生长因子23（FGF 23）的循环水平升高，FGF 23是磷酸盐稳态和维生素D代谢的关键内分泌调节剂。FGF 23升高是CKD患者和肾功能正常个体死亡的独立危险因素，但其潜在的生理机制尚不清楚。已知FGF 23抑制活性形式维生素D、1，25-二羟基维生素D（1，25（OH）2D）的肾合成，但其对其它外周组织的作用尚未确定。在体外的初步研究中，我们已经表明FGF 23抑制人单核细胞合成1，25（OH）2D，这表明内分泌和免疫系统之间存在全新的联系。我们假设CKD患者中FGF 23水平升高通过抑制单核细胞中的维生素D激活系统来抑制抗菌先天免疫应答。已知1，25（OH）2D的局部合成刺激抗菌蛋白如凯萨林菌素（LL 37）的产生，这可能是人类对感染作出反应的关键机制。因此，对于已经维生素D不足的CKD患者，免疫细胞暴露于高水平的FGF 23将为充分保护免受感染提供额外的障碍。拟议的项目将描述维生素D和FGF 23之间的关系，作为人类免疫力的积极和消极调节剂。计划的实验将确定FGF 23的抑制作用是否可以被活性1，25（OH）2D或其前体25-羟基维生素D（25 OHD）消除。通过这种方式，该提案将评估维持CKD患者最佳免疫功能的潜在治疗策略。该项目的进一步创新将通过使用外周血和腹膜单核细胞来提供。通过使用后者，我们的目标是确定维生素D作为人体抗菌功能的激活剂在组织部位的作用，那里是感染的高风险。总的来说，这些研究将寻求确定FGF 23在内分泌和免疫功能之间的界面上的全新功能。在这样做的过程中，该项目将有助于阐明一个关键机制，该机制可能解释FGF 23在CKD中的病理影响以及成人和儿童透析患者的高死亡率不变。