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Microcirculation in Renovascular Hypertension

肾血管性高血压的微循环

基本信息

批准号：
10670589
负责人：
Alejandro Roberto Chade
金额：
$ 50.72万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670589
关键词：
Microcirculation Renovascular Hypertension

项目摘要

Hypertension is the 2nd major etiology of chronic kidney disease (CKD), a progressive disorder affecting almost 14% of the general population. Patients with CKD in turn associates to hypertension (< 95%) and have higher rates of hospitalization, healthcare costs, cardiovascular mortality, and shorter life expectancy than non-CKD patients. Chronic renovascular disease (RVD) is the main cause of renovascular hypertension that develops in up to 11% of the US adults and increases risk of CKD by 25%. Despite the availability of treatments for RVD, renal function and hypertension do not improve or even deteriorates in over half of the patients, showing that treatments are still ineffective and highlighting the need of new treatments and strategies for these patients with higher mortality and risk of CKD. Our seminal work during the previous funding cycle of HL095638 showed that a progressive damage and loss of the renal microcirculation is a pivotal mechanism for renal injury and hypertension in RVD. We also showed that intra-renal single-dose therapy using recombinant human vascular endothelial growth factor (rh-VEGF) largely preserved the renal microcirculation and improved renal function in a swine model of RVD and hypertension. These effects were significant but still insufficient to fully reverse injury or hypertension despite VEGF being administered at an early stage of RVD. A potential reason for the incomplete resolution of renal damage is the short half-life of VEGF. Recently, we have developed a bioengineered protein polymer fused to rh-VEGF that greatly stabilizes VEGF from degradation and clearance. We showed that this protein-based polymer, called Elastin-like Polypeptide (ELP), naturally accumulates at high levels in the kidney. Our compelling preliminary data show that single intra-renal administration of an ELP- VEGF fusion improved renal function, microvascular injury, and hypertension in the swine RVD model more efficiently that free VEGF therapy. In addition, we developed engineered versions of the polymer, containing kidney targeting peptides (KTP) that further increase kidney deposition and specificity (KTP-ELP). Thus, the proposed studies in the renewal of HL095638 will extend the previous contributions by developing a new treatment with high potential for clinical translation. We recently developed and characterized a KTP-ELP- VEGF construct. This proposal will first assess the effectiveness of KTP-ELP to improve renal deposition and reduce off-target binding of VEGF. We will determine the specific intra-renal localization and cell-type binding in vitro and in vivo. We will use genetically modified mice models and a translational swine model of RVD and hypertension to collect pharmacokinetic, biodistribution, safety, and efficacy data needed to propel the advance of this technology towards clinical testing. Second, we will determine the therapeutic efficacy and mechanisms of renoprotection of minimally invasive single-dose intra-renal administration of KTP-ELP-VEGF to improve hypertension, renal function and microvascular injury. Finally, we will determine the efficacy and mechanisms of KTP-ELP-VEGF therapy after systemic, non-invasive, single-dose (repeated if needed) administration.

高血压是慢性肾脏病（CKD）的第二大病因，CKD是一种进行性疾病，占总人口的14%。CKD患者反过来与高血压相关（< 95%），住院率、医疗费用、心血管死亡率和预期寿命比非CKD患者短患者慢性肾血管病（RVD）是肾血管性高血压的主要原因，高达11%的美国成年人，并增加25%的CKD风险。尽管RVD的治疗方法是可行的，超过一半的患者的肾功能和高血压没有改善甚至恶化，这表明，治疗仍然无效，并强调需要为这些患者提供新的治疗和策略有更高的死亡率和CKD风险。我们在HL 095638上一个融资周期的开创性工作表明肾微循环的进行性损害和丧失是肾损伤的关键机制 RVD患者高血压。我们还表明，肾内单剂量治疗使用重组人血管内皮生长因子（rh-VEGF）在很大程度上保护了肾微循环，改善了肾功能。在RVD和高血压的猪模型中的功能。这些影响是显著的，但仍不足以充分逆转损伤或高血压，尽管在RVD的早期阶段施用VEGF。一个潜在的原因肾损伤不完全消退的原因是VEGF的半衰期短。最近，我们开发了一种与rh-VEGF融合的生物工程蛋白质聚合物，极大地稳定了VEGF的降解和清除。我们发现，这种蛋白质聚合物，称为弹性蛋白样多肽（ELP），自然积累，肾脏中的高水平。我们令人信服的初步数据表明，单次肾内给予ELP- VEGF融合改善了猪RVD模型的肾功能、微血管损伤和高血压，有效地释放VEGF。此外，我们开发了聚合物的工程版本，肾靶向肽（KTP），其进一步增加肾沉积和特异性（KTP-ELP）。因此 HL 095638更新中的拟议研究将通过开发新的具有高度临床转化潜力的治疗方法。我们最近开发并表征了KTP-ELP- VEGF构建体。该提案将首先评估KTP-ELP改善肾脏沉积的有效性，减少VEGF的脱靶结合。我们将确定特定的肾内定位和细胞类型结合在体外和体内。我们将使用转基因小鼠模型和转基因猪RVD模型，收集推动高血压进展所需的药代动力学、生物分布、安全性和疗效数据将这项技术用于临床试验。其次，我们将确定治疗效果和机制微创单剂量肾内给予KTP-ELP-VEGF的肾保护作用，高血压、肾功能和微血管损伤。最后，我们将确定疗效和机制在全身性、非侵入性、单次给药（如需要，重复给药）后，KTP-ELP-VEGF治疗。