HYALURONAN IN THE LUNG

项目4，Dweik)肺高压-特发性肺动脉高压(IPAH)中的透明质酸是一种进行性疾病，会导致心肺功能恶化和右室衰竭导致过早死亡。IPAH的发病机制尚不完全清楚。尽管肺动脉平滑肌细胞(PASMC)被认为是IPAH重塑过程中的主要成分，但触发和维持IPAH中PASMC增殖的原发异常的性质尚不清楚。我们最近发现并报告了一项新的发现，即PASMC自发地来自IPAH肺 Ipah患者血液中的透明质酸(HA)水平高于正常水平。我们假设，HA含量、修饰和碎裂的异常导致了主要的调控开关，这些开关指导着IPAH中异常的平滑肌细胞增殖、炎症和血管重塑。我们的具体目标是评估增加HA产量的机制 以及HA在维持IPAH的PASMC增殖、炎症和血管重塑方面所起的调节作用(S)。具体目标1：明确IPAH中PASMCs产生HA的调控机制(S)。 我们将评估从IPAH患者和对照组肺组织分离的PASMCs以及来自其他来源的平滑肌细胞(SMC)的不同Has和Hyal mRNAs和蛋白的表达，以及其他细胞类型的表达，以确定PASMCs的独特性。我们还将确定这些细胞中是否存在调节HA产生的遗传或表观遗传异常。具体目标2：确定HA在IPAH中的作用(S)。我们会通过研究高水平的HA在香港的功能后果来达到这一目标。 IPAH体内、外血管SMC的增殖和炎症反应。我们还将把HA水平与IPAH患者的疾病结局联系起来。具体目标3：揭示Ipah中HA增殖和促炎作用的机制(S)。我们将通过评估特定的HA修饰(S)来研究这一点，该修饰将正常生理条件下的这种主要结构分子转变为刺激IPAH肺细胞增殖和炎症的分子。

Project 4, Dweik) Hyaluronan in Pulmonary Hypertension - Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that leads to deterioration in cardiopulmonary function and premature death from right ventricular failure. The pathogenesis of IPAH is not fully understood. Although pulmonary artery smooth muscle cells (PASMCs) are considered a major component of the remodeling process in IPAH, the nature of the primary abnormality that triggers and perpetuates PASMC proliferation in IPAH is unclear. We have recently discovered and reported the novel finding that PASMCs from IPAH lungs spontaneously produce high levels of hyaluronan (HA) and that IPAH patients have higher than normal levels of circulating HA in their blood. We hypothesize that abnormalities in HA amount, modification, and fragmentation result in major regulatory switches directing abnormal smooth muscle cell proliferation, inflammation and vascular remodeling in IPAH. Our specific aims are designed to assess the mechanisms of increased HA production and the regulatory role(s) HA has in perpetuating PASMC proliferation, inflammation, and vascular remodeling in IPAH. Specific Aim 1: Define the mechanism(s) regulating HA production in PASMCs in IPAH. We will evaluate the expression of the different Has and Hyal mRNAs and proteins from PASMCs isolated from lungs of IPAH patients and controls, as well as for smooth muscle cells (SMCs) from other sources, and for other cell types to ascertain the uniqueness of the PASMCs. We will also determine if there are genetic or epigenetic abnormalities regulating HA production in these cells. Specific Aim 2: Determine the role(s) of HA in IPAH. We will accomplish this Aim by studying the functional consequences of the high levels of HA in vascular SMC proliferation and inflammation in IPAH in vivo and ex vivo. We will also correlate HA levels with disease outcomes in patients with IPAH. Specific Aim 3: Uncover the mechanlsm(s) responsible for the proliferative and pro-inflammatory functions of HA in IPAH. We will study this by evaluating the specific HA modification(s) that turn this primarily structural molecule under normal physiological conditions into a molecule that stimulates cell proliferation and inflammation in the IPAH lung.