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.
While it is currently recognized that cell proliferation and vascular remodeling are very important processes in the pathogenesis of IPAH, they remain poorly understood. The work proposed here will have a major impact not only on our understanding of the pathobiology of remodeling and cell proliferation in IPAH, but also on the development of better ways to diagnose, monitor and ultimately treat/cure IPAH.
|Alkhouri, N; Eng, K; Cikach, F et al. (2015) Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls. Pediatr Obes 10:23-9|
|Dababneh, Luma; Cikach, Frank; Alkukhun, Laith et al. (2014) Sublingual microcirculation in pulmonary arterial hypertension. Ann Am Thorac Soc 11:504-12|
|Foulcer, Simon J; Nelson, Courtney M; Quintero, Maritza V et al. (2014) Determinants of versican-V1 proteoglycan processing by the metalloproteinase ADAMTS5. J Biol Chem 289:27859-73|
|Dubail, Johanne; Aramaki-Hattori, Noriko; Bader, Hannah L et al. (2014) A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Genesis 52:702-12|
|Aytekin, Metin; Tonelli, Adriano R; Farver, Carol F et al. (2014) Leptin deficiency recapitulates the histological features of pulmonary arterial hypertension in mice. Int J Clin Exp Pathol 7:1935-46|
|Coulson-Thomas, Vivien Jane; Gesteira, Tarsis Ferreira; Hascall, Vincent et al. (2014) Umbilical cord mesenchymal stem cells suppress host rejection: the role of the glycocalyx. J Biol Chem 289:23465-81|
|Ghatak, Shibnath; Bogatkevich, Galina S; Atnelishvili, Ilia et al. (2014) Overexpression of c-Met and CD44v6 receptors contributes to autocrine TGF-?1 signaling in interstitial lung disease. J Biol Chem 289:7856-72|
|Navaneethan, Sankar D; Wehbe, Edgard; Heresi, Gustavo A et al. (2014) Presence and outcomes of kidney disease in patients with pulmonary hypertension. Clin J Am Soc Nephrol 9:855-63|
|Xu, Weiling; Janocha, Allison J; Leahy, Rachel A et al. (2014) A novel method for pulmonary research: assessment of bioenergetic function at the air-liquid interface. Redox Biol 2:513-9|
|Ghatak, Shibnath; Misra, Suniti; Norris, Russell A et al. (2014) Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis. J Biol Chem 289:8545-61|
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