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.

蒙克贝格的动脉硬化是一种血管硬化的形式，在中间发现钙沉积物弹性和肌肉动脉层，特别是在弹性纤维上，导致动脉僵硬和撕裂。一个糖尿病和慢性肾脏疾病患者心血管疾病的独立危险因素，使患者易于心血管死亡率和下肢截肢。没有治疗反向钙化。弹性蛋白蛋白的半衰期大于60年，几乎没有失误。在衰老和疾病期间过程，弹性纤维降解，容易钙化。我们已经开发了独特的纳米颗粒可以针对脉管系统中降解的弹性层降解，同时保留健康的动脉。这个项目集中通过靶向螯合剂乙二胺四乙酸（EDTA）去除矿物沉积物在动脉中降解并钙化弹性蛋白。然后，装有pentagalloyl葡萄糖（PGG）的纳米颗粒将是旨在密封钙结合位点，抑制酶促降解和恢复损失的弹性蛋白以改善血管弹性。我们强烈发布的数据表明，这种针对性的EDTA螯合疗法基于白蛋白纳米颗粒，逆转实验创建的血管钙化，并避免全身的副作用螯合疗法。我们想在慢性的临床相关动物模型中以这种方法前进腺嘌呤和高磷饮食引起的肾衰竭。在特定的目标1中，我们将测试以下假设：弹性特异性血管钙化的逆转是可能的当靶向纳米颗粒将螯合剂EDTA传递到大鼠模型中的血管钙化部位时引起血管钙化的腺嘌呤诱导的尿毒症。我们还将确定钙化是否回报通过监测动物长时间终止EDTA治疗后，这种疗法是否具有对骨密度和器官健康的任何不利影响。在特定目标2中，我们将检验双重假设携带EDTA的靶向NP的治疗（去除矿化）遵循NP携带PGG（阻止钙绑定位点）将防止血管钙化恢复并改善血管功能，而不论CKD 腺嘌呤诱导的尿毒症大鼠模型中的疾病。这种PGG疗法也将防止进一步的酶促血管平滑肌细胞的弹性蛋白和反向软骨/成骨的表型变化的降解。在特定目标3，使用遗传改变的小鼠，我们将测试以下假设。通过逆转VSMC稳定细胞样细胞过渡或通过从任何一个周细胞的新VSMC的培养基重新生产，内皮到间质转变（内托）或造血干细胞（HSC）迁移。通过成功完成这些研究，我们将首次开发针对性的疗法去除血管钙化的方法。这项研究，如果成功的话，将导致新的疗法来改善 CKD和血管钙化糖尿病患者的血管健康。