Medial Arterial Calcification: Mechanisms and Therapy

Monckeberg动脉硬化是一种血管硬化，其中在中膜中发现钙沉积， 弹性和肌肉动脉层，特别是在弹性纤维上，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， 使患者易于心血管死亡和下肢截肢。没有治疗方法 反向钙化弹性蛋白的半衰期>60年，几乎没有周转。在衰老和疾病期间 在这些过程中，弹性纤维降解并易于钙化。我们已经开发出独特的纳米颗粒， 可以靶向脉管系统中降解的弹性膜，同时保留健康的动脉。该项目的重点是 通过将螯合剂乙二胺四乙酸（EDTA）靶向于 动脉弹性蛋白降解和钙化。然后，将负载有五镓酰葡萄糖（PGG）的纳米颗粒 有针对性地密封钙结合位点，抑制酶降解，并恢复失去的弹性蛋白，以改善血管 弹性我们强有力的已发表数据表明，这种基于白蛋白的靶向EDTA螯合疗法， 纳米粒子，逆转实验创建的血管钙化，并避免全身化疗可能产生的副作用。 螯合疗法我们希望在临床相关的慢性炎症动物模型中采用这种方法。 腺嘌呤和高磷饮食引起的肾衰竭。 在具体目标1中，我们将检验弹性蛋白特异性血管钙化逆转是可能的这一假设 当靶向纳米颗粒将螯合剂EDTA递送到大鼠模型的血管钙化部位时， 腺嘌呤诱发的尿毒症会导致血管钙化我们还将确定钙化是否会恢复 EDTA治疗终止后，通过长时间监测动物，以及这种治疗是否 对骨密度和器官健康的任何不良影响。在具体目标2中，我们将测试双 在携带PGG（阻断钙）的NP之后，使用携带EDTA（去除矿化）的靶向NP进行治疗 结合位点）将防止血管钙化的恢复，并改善血管功能，无论是否患有CKD 在腺嘌呤诱导的尿毒症大鼠模型中的疾病。这种PGG疗法还将防止进一步的酶促反应。 弹性蛋白降解和血管平滑肌细胞的反向软骨/成骨表型改变。在 具体目标3，使用基因改变的小鼠，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导致血管稳态，或 通过用来自周细胞、内皮细胞向间充质细胞转化的新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，将导致新的疗法，以改善 CKD和糖尿病血管钙化患者的血管健康。

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.