HIPK2 signaling in Pulmonary Arterial Hypertension

肺动脉高压中的 HIPK2 信号传导

• 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
• 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

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)是一种进展性、致命性疾病，无法治愈。尽管最近进行了治疗 进展情况表明，PAH患者的预后仍然较差。PAH的主要病理特征是向内 小肺动脉(PA)重塑，至少部分是由于增殖增加和细胞减少 肺血管平滑肌细胞(PAVSMC)死亡(凋亡)。这导致了对 PA管腔，PA压力升高，以及右心衰竭死亡。PAVSMC的驱动机制 PAH中的过度增殖/存活和PA重塑尚不完全清楚，新的潜在抗PAH 迫切需要增殖分子靶点来开发有效的以重塑为重点的治疗方法来逆转 这种致命的疾病。同源结构域相互作用蛋白激酶2(HIPK2)是一种重要的细胞调节因子 增殖和存活，其调节失调与包括癌症在内的各种增殖性疾病有关。 然而，它的地位、作用、调节和功能的机制以及潜在的治疗吸引力 HIPK2对PAVSMC增殖、重塑和PAH的调节作用尚未见报道。我们的初步数据 结果显示，HIPK2在改建的小规模PAS的中层和高增殖、凋亡的PAS中层过表达。 人PAH肺来源的耐药PAVSMC及其过度表达是异常细胞增殖和 生死存亡。我们发现，HIPK2通过上调促增殖/促生存转录协同作用发挥作用。 激活剂YAP/TAZ和胞质分裂中心体蛋白55调节因子(CEP55)，CEP55反过来上调 AKT。重要的是，HIPK2的药理学靶向抑制了人PAH的增殖并诱导了其凋亡 PAVSMC，并减弱小鼠实验性PH，强烈提示HIPK2作为驱动因素的重要作用 PAH中PAVSMC的过度增殖和存活以及HIPK2作为一种重塑的潜在吸引力- 治疗干预的重点靶点。在这个提案中，我们将检验HIPK2上调的假设 在PAH-PAVSMC中，导致肺血管重构和PH，以及药物靶向 HIPK2抑制PAVSMC增殖，诱导细胞凋亡，重塑PAS，逆转或减弱 现有的PH值。具体地说，我们将(1)确定HIPK2在PAVSMC增殖、存活、 来自PAH和非疾病受试者的去识别肺组织和PAVSMC的重塑和PH(体外) 和条件性SM特异性Hipk2基因敲除转基因小鼠(体内)；(2)评价HIPK2的作用机制 (上调)PAH PAVSMC的调控，并剖析HIPK2-YAP/TAZ-CEP55-Akt轴内部的相互关系； 检测药物抑制HIPK2是否选择性抑制细胞增殖和诱导细胞凋亡 并逆转或减弱实验性肺血管重塑和肺血管重塑。 大鼠体内总体PH值。如果成功，这项拟议的研究将确定HIPK2在生长、增殖中的作用 和PAH PAVSMC的存活，确定HIPK2调控的主要信号通路，并评估其吸引力 HIPK2作为一种新的潜在分子靶点，用于开发抗PAH的新的抗增殖疗法。