Abnormal HIF signaling in Down syndrome-related pulmonary hypertension

项目总结 唐氏综合征(DS)是由21号染色体三倍体(HSA21)引起的疾病，发生在1：700活体 出生和出生是人类最常见的染色体异常。DS的一种主要共生情况是 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 当受到积极的治疗时。值得注意的是，PH在新生儿和患有DS的儿童中非常常见(28%) 与非DS受试者相比，可能与先天性心脏病有关。潜在的 DS中PH的原因和对加速PH的易感性仍然知之甚少，动物 对于DS的PH的临床前研究一直缺乏模型。最近的研究表明，早期的干扰 与血管生成和肺泡生长受损相关的肺发育异常在重度DS儿童中明显存在 PH，但仍有迫切需要确定延迟肺的特定遗传和分子机制 成熟并增加对PH的易感性。此外，需要更多选择性的PH疗法来减少 DS患者的心肺发病率和死亡率。过去的研究表明，患有DS的个体有低的 抗血管生成因子过度表达引起的血管疾病和实体瘤的发生率，但 肺血管生长受阻是血管生成及相关肺泡调节异常所致 DS儿童的生长发育和导致PH的机制仍不确定。我们的实验室有 先前证明，抑制血管生成途径会减少肺泡和血管的生长，并 在不同的实验模型中引起PH。此外，我们还发现HSA21编码的有效抗血管生成作用。 基因在人胎儿和新生儿肺中过表达，并显示血管和肺组织减少的证据 肺泡的生长，即使在没有心脏病的情况下。根据这些发现，我们的人类生物标记物研究 提示DS患儿血清抗血管生成因子水平与PH密切相关。我们的初步数据 结果显示，Dp16DS小鼠经过2周非常轻微的低氧暴露后，其PH值以升高为特征 肺血管壁增厚，血管密度降低，右室肥厚和延迟 肺成熟。在DS动物模型中，这种肺成熟和肺高压发育的延迟以前从未见过 研究表明，Dp16DS小鼠似乎是一种有效的DS中PH的临床前模型。低氧和低氧诱导 低氧诱导因子(HIF)信号在PH和肺发育异常中起关键作用，DS细胞的特征是假的 导致DS的各种功能缺陷的缺氧性状态。我们的初步数据显示，缺氧 可诱导基因网络显著上调，调节分子通路发生显著变化 在这个模型中，肺血管发育和对低氧的反应。因此，我们假设是温和的 Dp16新生小鼠低氧暴露可导致肺组织增生性疾病并延缓肺成熟 而这种异常的HIF信号是这一过程的关键驱动因素。总体而言，这些研究将提供新的 洞察DS中PH的风险，并潜在地确定未来治疗的新靶点。

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.