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The contributory role of microbial metabolite in the pathogenesis of CKD-dependent vascular calcification

微生物代谢产物在 CKD 依赖性血管钙化发病机制中的贡献作用

基本信息

批准号：
10064000
负责人：
Makoto Miyazaki
金额：
$ 46.92万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-22 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064000
关键词：
Affect Agonist Animal Model Attenuated Bacteria Bile Acids Blood Vessels Bone Density Cardiovascular Diseases Cardiovascular system Cause of Death Cell Culture Techniques Cells Cessation of life Chemicals Cholic Acids Chronic Kidney Failure Clostridium Collaborations Complementary DNA Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Deoxycholic Acid Forskolin G-Protein-Coupled Receptors GPBAR1 gene Gram-Positive Bacteria Human In Vitro Intestines Knockout Mice Lentivirus MYH11 gene Mediating Metabolic Metabolic Diseases Molecular Mus Nuclear Receptors Osteoblasts Osteogenesis Pathogenesis Pathway interactions Patients Phosphorylation Play Population Probiotics Process Production Receptor Activation Receptor Inhibition Reporting Repression Research Research Proposals Role Scheme Series Serum Signal Pathway Signal Transduction Smooth Muscle Myocytes Techniques Testing Vascular Smooth Muscle Vascular calcification WNT Signaling Pathway Wild Type Mouse calcification coronary artery calcification dehydroxylation epidemiology study gain of function gut bacteria gut microbiota high risk in vivo inhibitor/antagonist loss of function metabolomics microbial microbiome alteration microbiome composition mineralization mortality mouse model novel novel therapeutics osteogenic receptor small hairpin RNA transcription factor

项目摘要

The long term objective of this research proposal is to determine the molecular mechanisms of vascular calcification in order to identify novel target(s) for the treatment of chronic kidney disease (CKD)-dependent vascular calcification. Vascular calcification is closely associated with cardiovascular mortality in patients with CKD. In fact, more than half of all deaths in CKD patients can be attributed to cardiovascular diseases. Our previous study revealed that activation of a bile acid nuclear receptor, FXR, strongly attenuates CKD- dependent vascular calcification in animal models though an unknown mechanism. Recently, our metabolomic approach has identified that levels of a microbial bile acid metabolite, deoxycholic acid (DCA), are highly associated with an increased risk for higher coronary artery calcification (CAC) volumes and lower lumbar bone mineral density (BMD) in human patients and mice with CKD. We hypothesized that DCA generated by gram-positive bacteria causes CKD-dependent vascular calcification. Our hypothesis is also supported by the following evidence derived from a series of preliminary results from our lab: 1) CKD increases levels of circulating DCA. 2) FXR activation by its agonists preferentially reduces levels of DCA and a precursor of DCA, cholic acid. 3) FXR knockout mice with vascular calcification have significantly higher levels of DCA. 4) CKD alters gut bacteria populations and increases levels of the DCA-producing bacteria. 5) Activation of FXR normalizes the alteration of gut bacteria populations by CKD. 6) DCA but not other bile acids induces mineralization of VSMCs through TGR5-PKA--catenin signaling. To determine the pivotal role of microbial DCA in the pathogenesis of vascular calcification, we propose 3 specific aims: Specific Aim 1: Examine the molecular mechanism by which DCA induces vascular calcification in vitro. Specific Aim 2: A) Examine whether alterations of circulating DCA levels and gut bacteria populations influence CKD-dependent vascular calcification in vivo. B) Examine whether modulation of intestinal bacteria affects CKD-dependent vascular calcification in vivo. Specific Aim 3: Examine whether TGR5-PKA--catenin signaling contributes to CKD- dependent vascular calcification in vivo.

这项研究计划的长期目标是确定血管内皮细胞的分子机制，钙化，以确定用于治疗慢性肾脏病（CKD）依赖性血管钙化血管钙化与心血管疾病患者的死亡率密切相关， CKD。事实上，CKD患者中超过一半的死亡可归因于心血管疾病。我们先前的研究表明，胆汁酸核受体FXR的激活强烈减弱CKD，依赖性血管钙化的动物模型，虽然机制不明。最近，我们的代谢组学方法已经确定，微生物胆汁酸代谢物脱氧胆酸（DCA）的水平是高度与较高冠状动脉钙化（CAC）体积和较低的腰椎 CKD患者和小鼠的骨矿物质密度（BMD）。我们假设DCA产生于革兰氏阳性菌导致CKD依赖性血管钙化。我们的假设也得到了以下证据来自我们实验室的一系列初步结果：1）CKD增加了循环DCA。2)FXR通过其激动剂的激活优先降低DCA和DCA前体的水平，胆酸。3)具有血管钙化的FXR敲除小鼠具有显著更高水平的DCA。4)CKD 改变肠道细菌种群，增加DCA产生细菌的水平。5)的FXR活化使CKD引起的肠道菌群改变正常化。6)DCA而不是其他胆汁酸诱导通过TGR 5-PKA-β-连环蛋白信号转导促进VSMC矿化。为了确定微生物的关键作用， DCA在血管钙化的发病机制中，我们提出3个具体目标：具体目标1：检查 DCA在体外诱导血管钙化的分子机制。具体目标2：A）检查循环DCA水平和肠道细菌种群的改变是否影响CKD依赖性血管体内钙化。B）检查肠道细菌的调节是否影响CKD依赖性血管内皮细胞。体内钙化。具体目标3：检查TGR 5-PKA-β-连环蛋白信号传导是否有助于CKD-1。体内依赖性血管钙化。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Different effects of global osteopontin and macrophage osteopontin in glomerular injury.

DOI：
10.1152/ajprenal.00458.2017
发表时间：
2018-10
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
Jessica Trostel;L. Truong;Carlos Roncal-Jimenez;M. Miyazaki;Shinobu Miyazaki‐Anzai;M. Kuwabara;Rachel H
通讯作者：
Jessica Trostel;L. Truong;Carlos Roncal-Jimenez;M. Miyazaki;Shinobu Miyazaki‐Anzai;M. Kuwabara;Rachel H

Reduction of stearoyl-CoA desaturase (SCD) contributes muscle atrophy through the excess endoplasmic reticulum stress in chronic kidney disease.

降低甲酰基-COA去饱和酶（SCD）通过慢性肾脏疾病中过量的内质网应激造成肌肉萎缩。

DOI：
10.3164/jcbn.20-24
发表时间：
2020-09
期刊：
Journal of clinical biochemistry and nutrition
影响因子：
2.4
作者：
Niida Y;Masuda M;Adachi Y;Yoshizawa A;Ohminami H;Mori Y;Ohnishi K;Yamanaka-Okumura H;Uchida T;Nikawa T;Yamamoto H;Miyazaki M;Taketani Y
通讯作者：
Taketani Y

The CDK9-cyclin T1 complex mediates saturated fatty acid-induced vascular calcification by inducing expression of the transcription factor CHOP.

CDK9-CYCLIN T1复合物通过诱导转录因子CHOP的表达来介导饱和脂肪酸诱导的血管钙化。

DOI：
10.1074/jbc.ra118.004706
发表时间：
2018-11-02
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Shiozaki Y;Okamura K;Kohno S;Keenan AL;Williams K;Zhao X;Chick WS;Miyazaki-Anzai S;Miyazaki M
通讯作者：
Miyazaki M

The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.

DOI：
10.1016/j.cellsig.2020.109605
发表时间：
2020-07
期刊：
Cellular signalling
影响因子：
4.8
作者：
Brown CN;Atwood DJ;Pokhrel D;Ravichandran K;Holditch SJ;Saxena S;Miyazaki M;Nemenoff R;Weiser-Evans MCM;Ljubanovic DG;Joy MS;Edelstein CL
通讯作者：
Edelstein CL

Lipidomic insight into cardiovascular diseases.

对心血管疾病的脂质组学见解。