Basic Science Studies Completed Projects
Completed Projects Heading link
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Research by Chen, Tianji
Funder
Gilead
Goals
To investigate the role of miR-212 in pulmonary vascular smooth muscle and endothelial cells, and the transfer of miR-212 from endothelium to smooth muscle cells.
Description
Pulmonary hypertension (PH) is a devastating disease that results in a progressive increase in pulmonary vascular resistance, right ventricular failure, and ultimately death of patients. The endothelial and smooth muscle cells (EC and SMC) are two key cell types in the pulmonary vasculature. Crosstalk, like paracrine effects, between these two cell types plays an important role in maintaining the normal conditions of the vasculature and the pathogenesis of PH. However, the role of extracellular vesicle transfer between the two cell types and the exact mechanisms involved in the pathogenesis of PH are not well understood.
We found that under hypoxia, pulmonary artery EC (PAEC) release extracellular vesicles, specifically microvesicles (MV), that induce PASMC proliferation in vitro and PH in vivo, compared to that of normoxic PAEC. As we found that hypoxia exposure did not alter the number of PAECreleased MV, we reason that hypoxia exposure alters the cargo in PAEC-released MV and thereby their function to regulate PASMC proliferation and pathogenesis of PH. MicroRNAs (miRNAs, miRs) are small single-stranded non-coding RNAs and many of them have been identified to play important roles in disease development, including PH. Using miRNA deep sequencing analysis we found that, hypoxia exposure altered the miRNA cargo in PAEC-released MV: miR-210-3p level was increased, a miRNA that is known to stimulate SMC proliferation and induce PH. Meanwhile, hypoxia also induced a number of other miRNAs that inhibited SMC proliferation, principal among them being a novel miRNA, miR-212-5p, that had the highest inhibitory effect on SMC proliferation. Our data also showed that the endothelium and/or ECderived MV are critical for the induction of miR-212-5p in SMC in hypoxia as there was no induction of miRNA-212-5p in isolated SMC in hypoxia. Taking together, we hypothesize that EC-derived MV promote development of PH and vascular remodeling during hypoxia due to the presence of miRNA-210-3p but they may also provide a break against continued progression of the disease via anti-proliferative miRNAs, specifically miRNA-212-5p.
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Research by Raj, Usha and Zhou, Guofei
Description
This project aims to elucidate the molecular mechanisms underlying the microRNA-17~92/PDLIM5 signaling-mediated pulmonary artery smooth muscle cell phenotype change and its functional impact in the genesis of pulmonary hypertension. We are continuing to investigate the role of PDLIM5 in the metabolic shift and to carry out a PDLIM5-targeted drug development process for the treatment of pulmonary hypertension.
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Research by Rivers, Angela
Funder
NIH: NHLBI
Title
Mitophagy as Potential Target in Sickle Cell Disease
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Research by Raj, Usha and Chen, Tianji
Funder
American Heart Association
Goals
To investigate the role of pulmonary endothelium-derived microvesicles, and their miRNA cargos, in the pathogenesis of pulmonary vascular remodeling and pulmonary hypertension.
Description
In the pulmonary vasculature, the pulmonary vascular endothelial cells (PVEC) and pulmonary artery smooth muscle cells (PASMC) are two key cell types that play a major role in the pathobiology of pulmonary hypertension (PH). As the “signal initiator” in the pulmonary vasculature, PVEC affect the function of PASMC by secreting bioactive agents, myoendothelial injunctions (MEJ) and/or releasing extracellular vesicles (EV) that contain various cargo components including proteins and RNAs etc., under both normal and pathological conditions. So far, our knowledge about the role of endothelial-derived EV and its cargo in the PASMC function and pathogenesis of PH is very limited. In this proposal, we will investigate the role of PVEC-derived microvesicles (MV), especially that of the miRNA cargo in these MV, in the pathogenesis of pulmonary vascular remodeling and PH. In preliminary studies we found that in hypoxia, MV released by mouse PVEC in culture (H-MV) induced mouse PASMC proliferation in vitro and pulmonary vascular remodeling and PH in mice in room air (vs MV released by mouse PVEC in normoxia, H-MV vs N-MV). Using miRNA deep sequencing, we identified 9 miRNAs that were significantly induced in H-MV (v.s. N-MV), including miR-210, a miRNA that is known to induce SMC proliferation and PH. Interestingly, all the other identified miRNAs either suppressed or did not alter SMC proliferation in vitro, including a novel miRNA, miR-212-5p, that had the strongest inhibitory effect on SMC proliferation. We also found that miR-212-5p played a protective role in the pathogenesis of hypoxia-induced PH in mice. Based on these findings, we hypothesize that the endothelium, via MV, promotes vascular remodeling during hypoxia but also provides a break against continued progression of the disease via releasing anti-proliferative miRNAs, such as miR-212, packaged in the MV.
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Research by Raj, Usha and Zhou, Guofei
Funder
NIH: NHLBI
Description
This project aims to elucidate the molecular mechanisms underlying the microRNA-17~92/PDLIM5 signaling-mediated pulmonary artery smooth muscle cell phenotype change and its functional impact in the genesis of pulmonary hypertension. We are continuing to investigate the role of PDLIM5 in the metabolic shift and to carry out a PDLIM5-targeted drug development process for the treatment of pulmonary hypertension.
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Research by Raj, Usha and Chen, Tianji
Description
In this grant, the role of microRNAs and the endothelium derived extracellular vesicles in the pathogenesis of Pulmonary Hypertension is being studied. Another grant with this same title is developing a novel method of engineering the extracellular vesicles for treatment of pulmonary hypertension.
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Research by Reddy, Sekhar
Funder
NIH/NIGMS
Description
The counter balancing of pro- and anti-inflammatory gene transcription is crucial for normal homeostasis after septic tissue injury. Aberrant regulation of this transcriptional balance culminates in an unchecked systemic inflammation, leading to lung tissue damage and edema, respiratory failure and ultimately death. However, the exact mechanisms underlying pathological inflammation in sepsis are poorly understood, and thus the strategies to accelerate the resolution of sepsis are very limited. Studies in the proposal will test the novel hypothesis that pathogenic signaling caused by sepsis is the result of a macrophage-specific Fra-1/AP-1 restricted expression of anti- inflammatory A20, a crucial ubiquitin-editing enzyme that terminates uncontrolled activation of NF- κB and MAP kinase signaling. The proposed studies will offer novel insights and targets for therapies to accelerate lung injury repair in patients with pseudomonas pneumonia and sepsis.
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Research by Reddy, Sekhar
Funder
NIH: NHLBI
Title
Role of Nrf2 in Alveolar Epithelial Cell Regeneration During Lung Repair