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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.

蒙克伯格氏动脉硬化是血管硬化的一种形式，在血管内侧发现钙沉积