Medial Arterial Calcification: Mechanisms and Therapy

内侧动脉钙化：机制和治疗

基本信息

批准号：
10304908
负责人：
Naren R Vyavahare
金额：
$ 54.76万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304908
关键词：
Acetic Acids Acids Adenine Adopted Adverse effects Aging Albumins Amputation Animal Model Animals Arterial Fatty Streak Arteries Atherosclerosis Binding Binding Sites Blood Pressure Blood Vessels Bone Density Calcium Calcium Binding Cardiovascular Diseases Cardiovascular system Cathepsins Cells Chelating Agents Chelation Therapy Chronic Kidney Failure Complement Data Deposition Diabetes Mellitus Diabetic Nephropathy Diamines Diet Disease Disease-Free Survival Doppler Ultrasound Elastic Fiber Elasticity Elastin Endothelium Ethylenediamines Ethylenes Event Excision General Population Genetic Diseases Glucose Half-Life Health Hematopoietic stem cells Histology Homeostasis Human Hydroxyapatites Hypocalcemia Infiltration Injections Intravenous Isolated systolic hypertension Kidney Lead Lipids Lower Extremity Matrix Metalloproteinases Measures Mechanics Medial Mesenchymal Metabolic Diseases Methods Minerals Modeling Molecular Monckeberg Arteriosclerosis Monitor Morphology Mus Muscle Natural regeneration Organ Osteoblasts Pathology Patients Pericytes Periodicity Phenotype Phosphorus Physiologic pulse Process Proteins Publishing Pulse Pressure Quality of life Rattus Research Rodent Model Site Smooth Muscle Myocytes Testing Time Toxic effect Trace Elements Translating Tunica Adventitia Uremia Vascular Smooth Muscle Vascular calcification arterial stiffness base blood pressure elevation bone calcification cardiovascular risk factor cell transformation chemical binding clinically relevant controlled release diabetic diabetic patient dosage improved in vivo monitoring intima media macrophage mechanical properties mineralization mortality nanoparticle nanoparticle delivery novel therapeutics osteogenic prevent repaired seal side effect stem cell migration targeted treatment transdifferentiation

项目摘要

Monckeberg's arteriosclerosis is a form of vessel hardening in which calcium deposits are found in the medial layer of elastic and muscular arteries, specifically on elastic fibers, leading to arterial stiffening and tearing. An independent risk factor for cardiovascular diseases in diabetic and chronic kidney-disease patients, it predisposes patients to cardiovascular mortality and lower extremity amputation. There are no treatments to reverse calcification. Elastin protein has a half-life of >60 years with almost no turnover. During aging and disease processes, elastic fibers degrade and are prone to calcification. We have developed unique nanoparticles that can be targeted to degraded elastic lamina in vasculature while sparing healthy arteries. This project is focused on removing mineral deposits by targeting chelating agent ethylene diamine tetra acetic acid (EDTA) to the degraded and calcified elastin in arteries. Then, nanoparticles loaded with pentagalloyl glucose (PGG) will be targeted to seal calcium-binding sites, inhibit enzymatic degradation, and restore lost elastin to improve vascular elasticity. Our strong published data show that such targeted EDTA chelation therapy, based on albumin nanoparticles, reverses experimentally created vascular calcification and avoids possible side effects of systemic chelation therapy. We would like to take this approach forward in a clinically relevant animal model of chronic kidney failure caused by adenine and high phosphorus diet. In Specific Aim 1, we will test the hypothesis that reversal of elastin-specific vascular calcification is possible when targeted nanoparticles deliver a chelating agent, EDTA, to the site of vascular calcification in a rat model of adenine-induced uremia that causes vascular calcification. We will also determine whether calcification returns after termination of EDTA therapy by monitoring animals for extended periods and whether such therapy has any adverse effect on bone density and organ health. In Specific Aim 2, we will test the hypothesis that dual therapy of targeted NPs carrying EDTA (to remove mineralization) followed NPs carrying PGG (to block calcium binding sites) will prevent return of vascular calcification and improve vascular function irrespective of CKD disease in a rat model of adenine-induced uremia. Such PGG therapy will also prevent further enzymatic degradation of elastin and reverse chondro/osteogenic phenotypic change of vascular smooth muscle cells. In Specific Aim 3, using genetically altered mice, we will test the hypothesis that permanent reversal of calcification will lead to vascular homeostasis through reversing transdifferentiation of VSMC-osteoblast-like cell transition or by repopulation of media with new VSMCs from either pericytes, endothelial to mesenchymal transition (EndoMT), or hematopoietic stem cell (HSC) migration. With successful completion of these studies, we will, for the first time, have developed a targeted therapy approach to remove vascular calcification. This research, if successful, will lead to new therapies to improve vascular health in CKD and diabetic patients with vascular calcification.

蒙克伯格动脉硬化是血管硬化的一种形式，其中在内侧发现钙沉积。弹性和肌性动脉层，特别是弹性纤维，导致动脉硬化和撕裂。一个糖尿病和慢性肾病患者心血管疾病的独立危险因素使患者容易发生心血管死亡和下肢截肢。没有治疗方法逆转钙化。弹性蛋白的半衰期超过 60 年，几乎没有更新。在衰老和疾病期间过程中，弹性纤维会降解并容易钙化。我们开发了独特的纳米粒子可以针对脉管系统中退化的弹性层，同时保护健康的动脉。本项目重点通过将螯合剂乙二胺四乙酸（EDTA）靶向去除矿物质沉积物动脉中弹性蛋白的降解和钙化。然后，负载五没食子酰葡萄糖（PGG）的纳米颗粒将被旨在密封钙结合位点、抑制酶降解并恢复丢失的弹性蛋白以改善血管弹性。我们公布的强有力的数据表明，这种基于白蛋白的靶向 EDTA 螯合疗法纳米粒子，逆转实验产生的血管钙化，并避免全身可能的副作用螯合疗法。我们希望在临床相关的慢性病动物模型中推进这种方法腺嘌呤和高磷饮食引起的肾衰竭。在具体目标 1 中，我们将检验以下假设：弹性蛋白特异性血管钙化的逆转是可能的当靶向纳米粒子将螯合剂 EDTA 递送至大鼠模型中的血管钙化部位时腺嘌呤诱发的尿毒症导致血管钙化。我们还将确定钙化是否复发终止 EDTA 治疗后，通过长时间监测动物以及此类治疗是否已对骨密度和器官健康的任何不利影响。在具体目标 2 中，我们将检验对偶的假设携带 EDTA（以去除矿化）的靶向 NP 治疗，随后使用携带 PGG（以阻断钙离子）的 NP 治疗结合位点）将防止血管钙化复发并改善血管功能，无论是否有 CKD 腺嘌呤诱导的尿毒症大鼠模型中的疾病。这种 PGG 疗法还可以防止进一步的酶促作用。弹性蛋白的降解和逆转血管平滑肌细胞的软骨/成骨表型变化。在具体目标3，使用基因改造小鼠，我们将测试钙化永久逆转的假设将通过逆转 VSMC-成骨细胞样细胞转变的转分化来导致血管稳态，或通过从周细胞、内皮细胞到间充质转化的新 VSMC 重新填充培养基 (EndoMT) 或造血干细胞 (HSC) 迁移。随着这些研究的成功完成，我们将首次开发出一种靶向治疗方法去除血管钙化的方法。这项研究如果成功，将带来新的疗法来改善 CKD 和伴有血管钙化的糖尿病患者的血管健康。