Abnormal HIF signaling in Down syndrome-related pulmonary hypertension

项目摘要 唐氏综合征（DS）是由21号染色体（HSA 21）三倍体引起的疾病，发生在1：700的活 是人类最常见的染色体异常。DS的一个主要并发症是 肺动脉高压（PH），可导致进行性右心功能障碍、衰竭和死亡，甚至 当积极治疗。值得注意的是，PH在新生儿和DS儿童中非常常见（28%） 与非DS受试者相比，可能与先天性心脏病相关。底层 DS中PH的原因和对加速PH的敏感性增加仍然知之甚少， 一直缺乏用于DS中PH临床前研究的模型。最近的研究表明， 与血管生成和肺泡生长受损相关的肺发育的严重性在患有严重DS的儿童中是明显的。 PH，但仍然迫切需要确定延迟肺结核的特定遗传和分子机制， 此外，需要更有选择性的PH治疗来减少 心肺发病率和死亡率。过去的研究表明，患有DS的个体具有较低的 血管疾病和实体瘤的发病率由于抗血管生成因子的过度表达，但是否 肺血管生长的破坏是由于血管生成和相关肺泡 导致DS儿童PH的生长和机制仍然不确定。本实验室 先前证明，抑制血管生成途径会减少肺泡和血管生长， 在不同的实验模型中引起PH。此外，我们发现HSA 21编码的强效抗血管生成因子， 基因在人胎儿和新生儿DS肺中过表达，并显示出减少血管和 肺泡生长，即使没有心脏病。根据这些发现，我们的人类生物标志物研究 表明血清抗血管生成因子谱与DS儿童PH密切相关。我们的初步数据 显示Dp 16 DS小鼠2周的非常轻微的缺氧暴露导致PH，其特征在于增加的 肺血管壁增厚，血管密度降低和右心室肥大， 肺成熟在DS动物模型中，这种延迟的肺成熟和PH发展先前尚未被发现。 Dp 16 DS小鼠似乎是DS中PH的有效临床前模型。缺氧和缺氧诱导 (HIF)信号在PH和异常肺发育中是关键的，DS的细胞以假- 缺氧状态，导致DS中出现的各种功能缺陷。我们的初步数据显示缺氧 诱导型基因网络显著上调，其调节基因表达的分子途径发生显著改变。 肺血管发育和对缺氧的反应。因此，我们假设， Dp 16新生小鼠的缺氧暴露导致PH的发展并延迟肺成熟 而异常的HIF信号是这一过程的关键驱动力。总的来说，这些研究将提供新的 深入了解DS中PH的风险，并可能为未来的治疗确定新的靶点。

PROJECT SUMMARY Down syndrome (DS), the condition that arises from triplication of chromosome 21 (HSA21), occurs in 1:700 live births and is the most common human chromosomal abnormality. A major co-occurring condition in DS is pulmonary hypertension (PH), which can lead to progressive right heart dysfunction, failure, and death, even when aggressively treated. Remarkedly, PH occurs very frequently in newborns and children with DS (28%) when compared with non-DS subjects and can be associated with congenital heart disease. The underlying cause of PH and the increased susceptibility to accelerated PH in in DS remain poorly understood and animal models for preclinical studies of PH in DS have been lacking. Recent studies have shown that early disruption of lung development related to impaired angiogenesis and alveolar growth is evident in DS children with severe PH, but there remains a critical need to define specific genetic and molecular mechanisms that delay lung maturation and increase susceptibility for PH. Furthermore, more selective PH therapies are needed to decrease cardiopulmonary morbidity and mortality in DS. Past studies have suggested that individuals with DS have a low incidence of vascular disease and solid tumors due to overexpression of anti-angiogenic factors, but whether disruption of lung vascular growth is due to abnormal regulation of angiogenesis and related alveolar growth and mechanisms that contribute to PH in DS children remain uncertain. Our laboratory has previously demonstrated that inhibition of angiogenic pathways reduces lung alveolar and vessel growth and causes PH in diverse experimental models. Additionally, we showed that HSA21-encoded potent anti-angiogenic genes are overexpressed in human fetal and neonatal DS lung and show evidence for reduced vascular and alveolar growth, even in the absence of cardiac disease. In line with these findings, our human biomarker studies show that serum anti-angiogenic factor profile is strongly associated with PH in DS children. Our preliminary data show that 2 weeks of very mild hypoxia exposure of Dp16 DS mice leads to PH as characterized by increased pulmonary vascular wall thickening, decreased vascular densities and right ventricular hypertrophy, and delays lung maturation. Such delayed lung maturation and PH development in DS animal model has not been previously studied, and Dp16 DS mice appears to be a valid preclinical model of PH in DS. Hypoxia and hypoxia-inducible (HIF) signals are critical in PH and abnormal lung development, and cells of DS are characterized by pseudo- hypoxic state that drives a variety of functional deficits seen in DS. Our preliminary data show that hypoxia inducible gene network is markedly upregulated with significant alteration in the molecular pathways that regulate pulmonary vessel development and response to hypoxia in this model. Thus, we hypothesize that mild hypoxic exposure of Dp16 neonatal mice leads to the development of PH and delays lung maturation and that aberrant HIF signaling is a critical driver of this process. Overall, these studies will provide novel insights into the risk for PH in DS and potentially identify novel targets for future therapies.