HIPK2 signaling in Pulmonary Arterial Hypertension

肺动脉高压中的 HIPK2 信号传导

基本信息

批准号：
10565519
负责人：
Tatiana V Kudryashova
金额：
$ 41.5万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-20 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565519
关键词：
Abnormal Cell Apoptosis Area Attenuated Automobile Driving Cell Death Cell Proliferation Cell Survival Centrosome Cessation of life Cytokinesis Data Development Disease Disease Progression Distal Event Extracellular Matrix Growth Human Impairment In Vitro Induction of Apoptosis Knock-out Knowledge Link Lung Malignant Neoplasms Medial Modeling Molecular Molecular Target Mus Outcome Pathogenesis Pathologic Patients Phenotype Phosphotransferases Proliferating Protein Kinase Interaction Proteins Publishing Pulmonary Hypertension Pulmonary arterial remodeling Pulmonary artery structure Rattus Regulation Research Resistance Role Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Structure of parenchyma of lung Testing Therapeutic Therapeutic Intervention Tissue Sample Transcription Coactivator Transgenic Mice Up-Regulation Vascular Smooth Muscle Vascular remodeling Ventricular cell growth conditional knockout experimental study homeodomain improved in vivo insight molecular targeted therapies novel novel therapeutic intervention overexpression patient prognosis pharmacologic prevent pulmonary arterial hypertension pulmonary arterial pressure pulmonary vascular cells pulmonary vascular remodeling right ventricular failure targeted treatment tissue culture vascular factor vascular smooth muscle cell proliferation

项目摘要

PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive deadly disease with no cure. Despite recent therapeutic advances, the prognosis of patients with PAH remains poor. The key pathological feature of PAH is an inward remodeling of small pulmonary arteries (PA) due to, at least in part, increased proliferation and decreased cell death (apoptosis) of pulmonary arterial vascular smooth muscle cells (PAVSMC). This leads to obliteration of the PA lumen, elevated PA pressure, and death due to right heart failure. The mechanisms driving PAVSMC hyper-proliferation/survival and PA remodeling in PAH are not fully understood, and new potential anti- proliferative molecular targets are urgently needed to develop effective remodeling-focused therapies to reverse this deadly disease. Homeodomain-interacting protein kinase 2 (HIPK2) is an important regulator of cell proliferation and survival, dysregulation of which is linked with various proliferative disorders, including cancer. However, the status, role, mechanisms of regulation and function, and potential therapeutic attractiveness of HIPK2 to modulate PAVSMC proliferation, remodeling and PAH had never been studied. Our preliminary data show that HIPK2 is over-expressed in medial layer of small remodeled PAs and in hyper-proliferative, apoptosis- resistant PAVSMC from human PAH lungs and its overexpression is required for abnormal cell proliferation and survival. We found that HIPK2 acts through the up-regulation of pro-proliferative/pro-survival transcriptional co- activators YAP/TAZ and regulator of cytokinesis centrosomal protein 55 (CEP55), which, in turn, up-regulates Akt. Importantly, pharmacological targeting of HIPK2 reduced proliferation and induced apoptosis in human PAH PAVSMC, and attenuated experimental PH in mice, strongly suggesting the important role of HIPK2 as a driver of PAVSMC hyper-proliferation and survival in PAH and the potential attractiveness of HIPK2 as a remodeling- focused target for therapeutic intervention. In this proposal, we will test the hypothesis that HIPK2 is up-regulated in PAH PAVSMC, leading to pulmonary vascular remodeling and PH, and that pharmacological targeting of HIPK2 suppresses PAVSMC proliferation, induces apoptosis, re-remodels PAs and reverses or attenuates existing PH. Specifically, we will (1) determine the status and role of HIPK2 in PAVSMC proliferation, survival, remodeling and PH using de-identified lung tissues and PAVSMC fromPAH and non-diseased subjects (in vitro) and transgenic mice with conditional SM-specific Hipk2 knockout (in vivo); (2) evaluate the mechanisms of HIPK2 (up)regulation in PAH PAVSMC and dissect the interrelations within the HIPK2-YAP/TAZ-CEP55-Akt axis; (3) test whether pharmacological inhibition of HIPK2 selectively suppresses proliferation and induces apoptosis in vitro in human PAH PAVSMC, and reverses or attenuates experimental pulmonary vascular remodeling and overall PH in rats in vivo. If successful, the proposedstudy will define the function of HIPK2 in growth, proliferation and survival of PAH PAVSMC, identify main signaling pathways regulated by HIPK2, and evaluate attractiveness of HIPK2 as a new potential molecular target for development of novel anti-proliferative therapies for PAH.

项目摘要/摘要肺动脉高压（PAH）是一种进行性致命疾病，无法治愈。尽管最近治疗进步，PAH患者的预后仍然很差。 PAH的关键病理特征是向内小肺动脉（PA）的重塑，至少部分增加了增殖和细胞减少肺血管平滑肌细胞（PAVSMC）的死亡（凋亡）。这导致了 PA管腔，升高的PA压力和由于右心力衰竭而导致的死亡。驱动PAVSMC的机制尚未完全了解PAH中的高增殖/生存和PA重塑，而新的潜在抗 - 迫切需要增生的分子靶标，以开发有效重塑的疗法以逆转这种致命的疾病。同源域相互作用蛋白激酶2（HIPK2）是细胞的重要调节剂增殖和生存，其失调与包括癌症在内的各种增殖疾病有关。但是，调节和功能的状态，角色，机制以及潜在的治疗吸引力 HIPK2从未研究过调节PAVSMC增殖，重塑和PAH。我们的初步数据表明HIPK2在小重塑的PA的内侧层和过度增殖的凋亡 - 凋亡中过表达来自人类PAH肺的耐药PAVSMC及其过表达是异常细胞增殖所必需的生存。我们发现HIPK2通过对促生物/促生物生存的转录共同的上调起作用。激活剂YAP/TAZ和细胞因子中心蛋白55（CEP55）的调节剂，而后者又上调了 akt。重要的是，HIPK2的药理学靶向降低了人类PAH的增殖和诱导的凋亡 PAVSMC和减弱小鼠的实验pH值，强烈建议HIPK2作为驱动 PAVSMC超增殖和PAH中的存活以及Hipk2作为重塑的潜在吸引力集中于治疗干预的目标。在此提案中，我们将测试HIPK2上调的假设在PAH PAVSMC中，导致肺血管重塑和pH，并将药理学靶向 HIPK2抑制PAVSMC增殖，诱导凋亡，重新塑造PAS和逆转或减弱现有的ph。具体而言，我们将（1）确定HIPK2在PAVSMC增殖，生存中的状态和作用使用去识别的肺组织和PAVSMC进行重塑和pH，从PAH和非固定受试者（体外）和有条件的SM特异性HIPK2敲除（体内）的转基因小鼠；（2）评估HIPK2的机制（向上）调节PAH PAVSMC并剖析HIPK2-YAP/TAZ-CEP55-AKT轴内的相互关系；（3）测试HIPK2的药理学抑制是否有选择地抑制增殖并诱导凋亡人类PAH PAVSMC的体外，逆转或减弱实验性肺血管重塑和体内大鼠的总pH。如果成功，则提出的研究将定义HIPK2在生长，增殖中的功能 PAH PAVSMC的生存，识别由HIPK2调节的主要信号通路，并评估吸引力 HIPK2是PAH新型抗增殖疗法的开发的新的潜在分子靶标。