Consequences of Elevated Fibroblast Growth Factor 23 in the Presence and Absence of Kidney Disease

成纤维细胞生长因子 23 升高对存在和不存在肾脏疾病的影响

基本信息

批准号：
9751287
负责人：
jyothsna gattineni
金额：
$ 32.09万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-26 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751287
关键词：
Adenine Adverse effects Affect Age-Months Animal Model Animals Aorta Biology CRISPR/Cas technology Calcium Cardiac Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Chondrocyte-like Cell Chronic Chronic Kidney Failure Comorbidity Conflict (Psychology)Data Development Dialysis procedure Diet Diet Modification Direct Lytic Factors End stage renal failure Epidemic Etiology Exposure to Fibroblast Growth Factor Fibroblast Growth Factor Receptors General Population Genes Goals Health Heart Hormones Human Hypophosphatemia In Vitro Individual Inflammation Kidney Kidney Diseases Kidney Failure Knowledge Laboratories Left Ventricular Hypertrophy MAP Kinase Gene Medial Mediating Mission Modeling Morbidity - disease rate Mus Myocardial dysfunction Neurocognitive Observational Study Organ Outcome Pathologic Pathway interactions Patients Phenotype Physiologic calcification Plasma Public Health Regimen Renal function Research Proposals Resistance Role Serum Signal Pathway Signal Transduction Smooth Muscle Myocytes Testing Toxin Treatment Efficacy United States United States National Institutes of Health Uremia Vascular Smooth Muscle Vascular calcification Wild Type Mouse bone bone health calcification cardiovascular risk factor epidemiology study fibroblast growth factor 23 improved in vivo innovation inorganic phosphate kidney dysfunction kidney fibrosis knock-down modifiable risk mortality mortality risk mouse model new therapeutic target receptor receptor expression smoothened signaling pathway therapeutic target translational impact uremic cardiomyopathy

项目摘要

PROJECT SUMMARY Chronic kidney disease has become a worldwide epidemic with approximately 26 million people being affected in the United States alone. The primary cause of death in patients with chronic kidney disease (CKD)/ end stage renal disease (ESRD) is from uremic cardiomyopathy and medial vascular calcification resulting in cardiovascular death (CVD). The etiology of CVD in CKD/ESRD is multifactorial, and despite advances made in treating the associated co-morbidities, the survival of patients with CKD/ESRD has not significantly improved. Fibroblast growth factor 23 (FGF23), a phosphaturic hormone secreted by the bone, is elevated early in CKD to maintain normophosphatemia, and, continues to increase with progression of CKD to ESRD to supraphysiological levels. Epidemiological studies have associated FGF23 with increased cardiovascular mortality/morbidity in CKD/ESRD. However, there is conflicting data regarding the direct effects of FGF23 on the heart and the vasculature using animal models and human observational studies. Thus, the biology of FGF23 is poorly understood and there is a need to determine the effects of FGF23 on the cardiovascular system in kidney disease. The applicant's laboratory has developed an innovative mouse model with a compound deletion of fibroblast growth factor receptors (Fgfrs) in the kidney: Kidney Conditional Fgfr1 and Fgfr4 (KCFgfr1-/-/Fgfr4-/- mice) which results in chronic elevation of FGF23 levels without hypophosphatemia due to renal resistance to the phosphaturic actions of FGF23. The applicant's long term goal is to identify the role of FGF23 in health and kidney disease especially in regards to development/progression of CKD, renal fibrosis, inflammation, bone mineralization, and neurocognitive functions. Using the above described mouse model, the overall objective for this proposal is to identify the direct effects of FGF23 on the cardiovascular system in kidney disease. Our preliminary data indicates that there is increased cardiac mass with chronic exposure to FGF23 together with hyperphosphatemia at 6 months of age and there is increased aortic calcification in 12-18 month old mice. We will determine the additional factors that FGF23 requires to cause increased cardiac mass as KCFgfr1-/-/Fgfr4-/- mice have modest hyperphosphatemia, as seen in kidney disease. We will use different dietary regimens to tease out which additional factors are required for FGF23 to have the adverse effects on the heart: hyperphosphatemia, uremic toxins or a combination of both. With this research proposal, we will also study the signaling pathways responsible for conversion of vascular smooth muscle cells into a chondrocyte-like cells promoting vascular calcification. We aim to identify the Fgfrs responsible for promoting vascular calcification in addition to the signaling pathways. The results from this proposal will offer avenues for new therapeutic targets to mitigate the effects of FGF23 on the cardiovascular system which will have a positive impact on the cardiovascular mortality/morbidity of patients with CKD/ESRD.

项目概要慢性肾病已成为全球流行病，约有 2600 万人受到影响仅在美国。慢性肾病（CKD）患者的主要原因死亡/结束终末期肾病 (ESRD) 是由尿毒症心肌病和内侧血管钙化导致的心血管死亡（CVD）。 CKD/ESRD 中的 CVD 病因是多因素的，尽管取得了进展在治疗相关合并症时，CKD/ESRD 患者的生存率并没有显着提高。改善了。成纤维细胞生长因子 23 (FGF23)（一种由骨骼分泌的磷酸盐激素）升高在 CKD 早期维持正常磷血症，并且随着 CKD 发展为 ESRD 继续增加超生理水平。流行病学研究表明 FGF23 与心血管疾病增加有关 CKD/ESRD 的死亡率/发病率。然而，关于 FGF23 对健康的直接影响存在相互矛盾的数据。使用动物模型和人体观察研究来研究心脏和脉管系统。因此，生物学 FGF23 人们知之甚少，需要确定 FGF23 对心血管的影响肾脏疾病的系统。申请人的实验室开发了一种创新的小鼠模型，其具有肾脏中成纤维细胞生长因子受体 (Fgfrs) 的复合缺失：肾脏条件性 Fgfr1 和 Fgfr4（KCFgfr1-/-/Fgfr4-/- 小鼠）导致 FGF23 水平慢性升高，但无低磷血症由于肾脏对 FGF23 的磷酸盐作用产生抵抗。申请人的长期目标是确定 FGF23 在健康和肾脏疾病中的作用，特别是在 CKD、肾病的发展/进展方面纤维化、炎症、骨矿化和神经认知功能。使用上述鼠标模型，该提案的总体目标是确定 FGF23 对心血管的直接影响肾脏疾病的系统。我们的初步数据表明，慢性心脏疾病导致心脏质量增加。 6 个月大时暴露于 FGF23 并伴有高磷酸盐血症，主动脉血压升高 12-18个月大的小鼠钙化。我们将确定 FGF23 需要引起的其他因素心脏质量增加，因为 KCFgfr1-/-/Fgfr4-/- 小鼠有适度的高磷酸盐血症，如肾脏中所见疾病。我们将使用不同的饮食方案来梳理 FGF23 需要哪些额外因素对心脏有不利影响：高磷血症、尿毒症毒素或两者的组合。有了这个研究计划中，我们还将研究负责血管平滑肌转化的信号通路肌细胞转变为软骨细胞样细胞，促进血管钙化。我们的目标是识别 Fgfrs 除了信号通路外，还负责促进血管钙化。由此得出的结果该提案将为新的治疗靶点提供途径，以减轻 FGF23 对心血管的影响该系统将对 CKD/ESRD 患者的心血管死亡率/发病率产生积极影响。