Lung inflammation and hypoxemia are major risk factors for mortality in acute respiratory distress syndrome, a disorder characterized by mortality that by some estimates can exceed 40%. Sepsis, a severe inflammatory disorder, is the primary cause of morbidity and mortality in these patients. Impaired gas exchange and hypoxemia define this severe respiratory illness and matching of ventilation and perfusion in the lung microenvironment is crucial for adequate gas exchange. Impaired hypoxic pulmonary vasoconstriction (HPV) results in ventilation and perfusion mismatching leading to hypoxemia and impaired HPV has been implicated in multiple pulmonary diseases associated with inflammation, including sepsis and acute lung injury. The current proposal focuses on the role of nuclear factor of activated T-cells (NFAT) in impaired hypoxic pulmonary vasoconstriction (HPV) during acute lung injury and inflammation. NFAT is a transcription factor that translocates to the nucleus after phosphate cleavage by calcineurin, as calcium dependent phosphatase, where it transcriptionally regulates numerous gene targets. NFAT has been implicated in multiple inflammatory disease processes including experimental animal models of sepsis and ALI. TRPC channels are an essential factor in intracellular calcium influx and signaling that is crucial for pulmonary vasoreactivity. Our preliminary data suggests that LPS-induced lung injury leads to NFAT activation and impaired hypoxic pulmonary vasoconstriction, potentially due to downregulation of TRPC channels. We hypothesize that acute lung inflammation causes impaired HPV and downregulated TRPC channel expression and function leading to hypoxemia in ARDS patients. The inflammation- mediated TRPC channel downregulation is due to NFAT-mediated epigenetic modifications which can be targeted in experimental animal models and in vivo preparations. We will use specific aims in order to define this relationship.
In Aim 1 we will determine the effects of lung inflammation and NFAT activation on pulmonary artery smooth muscle cells and pulmonary vasoreactivity.
In Aim 2 we will determine the epigenetic mechanisms responsible for changes in the PASMC and pulmonary vasoreactivity due to NFAT activation.
In Aim 3 we will determine the effects of inflammation, NFAT activation, and epigenetic modifications in a novel in vivo mouse preparation. In addition to the research proposal, a detailed training plan has been proposed in order to facilitate the development of a successful career as a physician-scientist. We describe how mentorship will foster skills in research methods, writing development, and career advancement through protected research time, didactic learning, peer recognition, intramural and extramural training, authorship, collaboration and future grant development. We have proposed a graded structure in which research activities which represent at least 75% time commitment initially have a strong emphasis on course work and learning opportunities which gradually evolves into more time spent on the research project, manuscript publication, and R01 development. Our long-term goals are to define the mechanisms of impaired HPV in lung inflammation in order to identify novel molecular targets to enhance V/Q matching and gas exchange in the lung. With this proposal I hope to strengthen my knowledge and technical skills in pulmonary vascular disease research in order to facilitate my development as an independent investigator and successful physician-scientist.
Lung inflammation and hypoxemia are major risk factors for mortality in acute respiratory distress syndrome (ARDS). Adequate blood oxygenation is dependent on effective matching of ventilation and perfusion in the lung microenvironment and, as an evolutionary mechanism, hypoxic pulmonary vasoconstriction is aimed at maintaining sufficient blood supply to the most effectively ventilated areas of the lung. The purpose of this proposal is to determine the mechanisms by which NFATc3 leads to impaired HPV during acute lung inflammation and injury.
|Fraidenburg, Dustin R; Machado, Roberto F (2018) A Review of Transcriptome Analysis in Pulmonary Vascular Diseases. Methods Mol Biol 1783:259-277|
|Zhou, Tong; Tang, Haiyang; Han, Ying et al. (2017) Expression profile of mitochondrial voltage-dependent anion channel-1 (VDAC1) influenced genes is associated with pulmonary hypertension. Korean J Physiol Pharmacol 21:353-360|
|Ren, Xingsheng; Zhang, Feng; Zhao, Mingxia et al. (2017) Angiotensin-(1-7) in Paraventricular Nucleus Contributes to the Enhanced Cardiac Sympathetic Afferent Reflex and Sympathetic Activity in Chronic Heart Failure Rats. Cell Physiol Biochem 42:2523-2539|
|Guo, Qiang; Huang, Jian-An; Fraidenburg, Dustin R (2014) Bosentan as rescue treatment in refractory hypoxemia and pulmonary hypertension in a patient with ARDS and H7N9 influenza virus infection. Lung 192:635-6|