Apoptosis-based therapy to treat pulmonary hypertension

项目摘要/摘要 肺动脉高压(PAH)是一种无法治愈的致命疾病。这是一种进行性疾病，可以 影响任何年龄段的个人，包括儿童和年轻人。当患者被诊断出患有这种疾病时 随着疾病的发展，肺动脉壁增厚往往已经发展起来。增加的阻力 肺循环在右室(RV)上留下斑点，导致右心衰竭和死亡， 如果不治疗，确诊后平均总存活率为2-3年。目前可用的治疗方法包括 血管扩张剂对这些患者的存活率影响有限。因此，消除过剩的代理 肺血管细胞具有治疗潜力，因为它们能够减少血管壁厚度和 从而降低肺血管阻力。在这方面，基于细胞凋亡的疗法用于治疗 癌症可能对治疗PAH有用。然而，凋亡剂也可能产生心脏毒性， 这使得针对患有RV的PAH患者的这种治疗方法的开发变得复杂起来 受压力过载的影响。我的长期目标是开发基于细胞凋亡的治疗策略 在不促进心肌细胞死亡的情况下减少肺血管壁厚度。这场比赛的目的是 更新应用是评估用于癌症治疗的凋亡剂的逆转效果 肺血管壁增厚及其对右室功能的影响 高血压。中心假设是促进程序化细胞的癌症化疗药物 死亡可以用来逆转肺血管壁增厚，而不会对肥厚的人产生不利影响 RV在一定的治疗条件下。这一假设是在初步数据的基础上提出的 已证明：(1)用于癌症化疗的药物，如蒽环类药物和蛋白酶体 抑制剂可降低大鼠和小鼠的肺血管壁厚度，但不能 在正常动物中；(Ii)心肌细胞和肺血管平滑肌细胞有不同 细胞程序性死亡的机制；以及(Iii)肥厚的RV上调了细胞的存活 机械装置。这项拟议研究的基本原理是，一旦理解了细胞是如何 在肺血管和心脏已经获得了区别杀死，这将导致新的战略 在不影响心脏的情况下，减少肺血管壁厚度。此应用程序的目标将是 通过追求两个特定的目标来完成：1)确定肺功能减退的机制 基于细胞凋亡的治疗药物导致的血管壁增厚；以及2)确定基于细胞凋亡的效应 心脏治疗药物，包括肥厚的RV。拟议的工作具有创新性，因为它将 探讨肺血管壁增厚逆转的机制，解决 心脏毒性在影响肺血管系统的背景下，从根本上提高了对 右心生物学迄今研究不足，并提供了细胞死亡的新机制。这些 结果将是重要的，因为他们有望提供新的治疗策略来治疗患者 啊哈。

Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. It is a progressive disease that can affect individuals of any age, including children and young adults. By the time patients are diagnosed with this disease, the thickening of pulmonary arterial walls has often already developed. Increased resistance in pulmonary circulation places stain on the right ventricle (RV), which leads to right heart failure and death, with a mean overall survival of 2-3 years after diagnosis if untreated. The currently available therapies with vasodilators have only limited effects on the survival of these patients. Therefore, agents that eliminate excess pulmonary vascular cells have therapeutic potential due to their ability to reduce vascular wall thickness and thereby decrease pulmonary vascular resistance. In this regard, apoptosis-based therapies used to treat cancer may be useful for the treatment of PAH. Apoptotic agents, however, could also exert cardiotoxicity, which complicates the development of such a therapeutic approach for PAH patients with RVs that have been affected by pressure overload. My long-range goal is to develop apoptosis-based therapeutic strategies to reduce pulmonary vascular wall thickness without promoting cardiac cell death. The objective of this competing renewal application is to evaluate the effectiveness of apoptotic agents used for cancer therapy in reversing pulmonary vascular wall thickening and their effects on the RV using preclinical models of pulmonary hypertension. The central hypothesis is that cancer chemotherapeutic agents that promote programmed cell death can be used to reverse pulmonary vascular wall thickening without adversely affecting the hypertrophied RV under certain therapeutic conditions. This hypothesis has been formulated on the basis of preliminary data that have demonstrated that: (i) agents used in cancer chemotherapy, such as anthracyclines and proteasome inhibitors, reduce the thickness of pulmonary vascular walls in pulmonary hypertensive rats and mice, but not in normal animals; (ii) heart muscle cells and pulmonary vascular smooth muscle cells have different mechanisms of programmed cell death; and (iii) the hypertrophied RV has upregulated cell survival mechanisms. The rationale for the proposed research is that once an understanding of how cells are differentially killed in the pulmonary vasculature and the heart has been obtained, it will lead to new strategies to reduce pulmonary vascular wall thickness without affecting the heart. The objective of this application will be accomplished by pursuing two specific aims: 1) Identify the mechanism of the regression of pulmonary vascular wall thickening by apoptosis-based therapeutic agents; and 2) Define the effects of apoptosis-based therapeutic agents on the heart, including hypertrophied RV. The proposed work is innovative because it will investigate the mechanism of the reversal of pulmonary vascular wall thickening, address the issue of cardiotoxicity in the setting of affecting the pulmonary vasculature, fundamentally advance the knowledge of right heart biology that has been understudied to date, and provide novel mechanisms of cell death. These results will be significant because they are expected to provide new therapeutic strategies to treat patients with PAH.