Medial Arterial Calcification: Mechanisms and Therapy

Monckeberg氏动脉硬化是一种血管硬化形式，其内侧可见钙沉积。 弹性动脉和肌肉动脉的一层，特别是弹性纤维上，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 容易导致心血管疾病死亡和截肢。没有任何治疗方法可以治疗 反向钙化。弹性蛋白的半衰期为60年，几乎没有周转。在衰老和疾病期间 过程中，弹性纤维会降解，并容易钙化。我们已经开发出独特的纳米颗粒， 可以针对血管系统中降解的弹性板层，同时保留健康的动脉。这个项目是专注于 以乙二胺四乙酸(EDTA)为靶标清除矿床的研究 动脉中降解和钙化的弹性蛋白。然后，负载五合金基葡萄糖(PGG)的纳米颗粒将被 旨在封闭钙结合部位，抑制酶降解，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 纳米颗粒，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阻塞性肺疾病动物模型中推进这一方法。 腺嘌呤和高磷饮食引起的肾功能衰竭。 在特定的目标1中，我们将检验弹性蛋白特异的血管钙化逆转是可能的假设。 当靶向纳米颗粒将螯合剂EDTA输送到大鼠模型的血管钙化部位时 导致血管钙化的腺嘌呤尿毒症。我们还将确定钙化是否会恢复 在EDTA治疗终止后，通过延长动物监测时间以及这种治疗是否有 对骨密度和器官健康有任何不良影响。在具体目标2中，我们将检验DUAL的假设 靶向携带EDTA的NPs和携带PGG的NPs的治疗 结合部位)将防止血管钙化复发并改善血管功能，而与CKD无关 腺嘌呤诱导的尿毒症大鼠模型中的疾病。这样的PGG治疗也将防止进一步的酶 弹性蛋白的降解和血管平滑肌细胞软骨/成骨表型的逆转变化。在……里面 具体目标3，使用基因改变的小鼠，我们将检验永久逆转钙化的假设 将通过逆转VSMC-成骨细胞样细胞转化的转分化而导致血管内稳态 通过将新的VSMCs从周细胞、内皮细胞到间充质细胞重新填充到基质中 (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有针对性的治疗方法。 去除血管钙化的方法。这项研究如果成功，将导致新的治疗方法得到改进 慢性肾脏病和糖尿病合并血管钙化患者的血管健康状况。

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.