The role of MLKL in the regulation of vascular calcification in CKD

MLKL 在 CKD 血管钙化调节中的作用

• 批准号: 10362295
• 负责人: Makoto Miyazaki
• 金额: $ 55.24万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362295
• 关键词: Affect; Aorta; Apoptosis; Apoptosis Inhibitor; Attenuated; Blood Vessels; CASP8 gene; Cardiovascular Diseases; Cause of Death; Cell Culture Techniques; Cell Death; Cells; Chemicals; Chronic; Chronic Kidney Failure; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Cultured Cells; Data; Disease model; Event; Goals; In Vitro; Indoles; Inflammation; Inflammatory; Laboratories; Libraries; Link; Lipids; Medial; Mediating; Metabolism; Minerals; Molecular; Morbidity - disease rate; Mus; Osteoblasts; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phosphorus; Phosphorylation; Play; Prevention strategy; Process; Publications; RIPK1 gene; RIPK3 gene; Regulation; Research Project Grants; Role; Scheme; Series; Serum; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stress; TLR4 gene; TNF gene; TNFRSF1A gene; Techniques; Testing; Toxin; Transcriptional Activation; Vascular Smooth Muscle; Vascular calcification; Vesicle; base; biological adaptation to stress; calcification; cytokine; effective therapy; endoplasmic reticulum stress; in vivo; in vivo Model; inflammatory marker; inhibitor; mineralization; mortality; mouse model; new therapeutic target; novel; osteoblast differentiation; overexpression; screening; small molecule libraries

Cardiovascular diseases such as vascular calcification are a leading cause of death in patients with chronic kidney disease (CKD). However, there is no effective therapy for vascular calcification available. In addition to uremic toxins such as indoles and phosphorus, inflammatory cytokines such as TNF play a major causative role in the regulation of CKD-dependent vascular calcification. Our long-term goal is to identify new pharmacological strategies for the prevention of vascular calcification. Our studies have demonstrated that simultaneous activation of the endoplasmic reticulum (ER) stress and IKK-NFB-inflammation pathways in vascular smooth muscles cells (VSMCs) are major events in the induction of vascular calcification in CKD. We have also revealed that ER stress-mediated integrated stress signal (ISR) in VSMCs plays a causative role in the pathogenesis of vascular calcification. Unexpectedly, however, the inhibition of IKK-mediated inflammation drastically exacerbated vascular calcification in CKD mice. In addition, both ER stress-ISR (ATF4-CHOP) activation- and IKK inhibition-mediated vascular calcification are highly associated with vascular cell death. There results led us to hypothesize that one of the regulated cell death (RCD) pathways is a major player in the initiation of vascular calcification. To find clues about the mechanism, we recently screened a library of chemicals that inhibit RCD. Based on the RCD chemical library screening, we identified an RCD pathway that selectively contributes to IKK inhibition-induced and CHOP-induced vascular calcification. We therefore propose two specific aims to elucidate. Aim 1 will examine whether the RCD pathway affects vascular calcification by altering the secretion of calcifying macrovesicles in cultured cells. Aim 2 will examine whether modulation of the RCD pathway affects CKD-dependent vascular calcification in vivo. Completion of this project will provide novel therapeutic targets for CKD-mediated vascular calcification.

心血管疾病如血管钙化是慢性阻塞性肺疾病患者死亡的主要原因。 肾病（CKD）。然而，目前尚无有效的治疗血管钙化的方法。除了 尿毒症毒素如吲哚和磷，炎性细胞因子如TNF α起主要致病作用 在调节CKD依赖性血管钙化中的作用。我们的长期目标是确定新的 预防血管钙化的药理学策略。我们的研究表明， 同时激活内质网（ER）应激和IKK κ B-NF κ B-炎症通路， 血管平滑肌细胞（VSMC）是CKD中诱导血管钙化的主要事件。我们 还揭示了VSMCs中ER应激介导的整合应激信号（ISR）在VSMCs中起着致病作用， 血管钙化的发病机制。然而，出乎意料的是，IKK β介导的抑制 炎症大大加剧了CKD小鼠的血管钙化。此外，ER应力-ISR （ATF 4-CHOP）激活和IKK抑制介导的血管钙化与 血管细胞死亡这些结果使我们假设，其中一个调节性细胞死亡（RCD）途径是 是血管钙化的主要原因为了找到机制的线索，我们最近 筛选了一个抑制RCD的化学物质库。基于RCD化学文库筛选，我们鉴定了 一种选择性促进IKK β抑制和CHOP诱导的血管生成的RCD通路 钙化因此，我们提出了两个具体的目的，以澄清。目标1将审查刚果民盟是否 通过改变培养细胞中钙化大泡的分泌来影响血管钙化。目的 2将检查RCD通路的调节是否影响体内CKD依赖性血管钙化。 该项目的完成将为CKD介导的血管钙化提供新的治疗靶点。