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The role of mitochondrial autophagy in supressionvascular remodeling of pulmonary hypertension
China (IFMSA-China) - Nanjing Medical University, Nanjing
Department of ForensicMedicine
Type of Research Project
- Basic science
What is the background of the project?
Pulmonary hypertension (PH) is a devastating syndrome with high mortality, affecting both pediatric and adult patients with a wide variety of disorders. Pulmonary hypertension has a rapid progression and a poor prognosis, and there is currently no specific intervention therapy. Mitochondrial dysfunction is thought to be related to the pathogenesis of PH. In our previous study, we had found that in PH mitophagy of abnormal mitochondria was suppressed. So, we want to explore that whether recovery of mitophagy could inhibit the development of PH. Several molecules were involved in mitophagy, Pink1 recruits and phosphorylates Parkin to mediate normal mitophagy. At the same time, HSP90 stress expression increased in the hypoxia model. The expression of Galectin-3 was also confirmed to be significantly elevated in pulmonary hypertension. Heat shock protein 90 is a group of highly conserved proteins that are widely involved in cell development, growth and differentiation as molecular chaperones. Galectin-3 (Gal-3) is a member of the galectin protein family. Gal-3 plays an important role in normal and pathological tissues, and can regulate cell proliferation, adhesion, differentiation, angiogenesis and apoptosis. Confirming the role of mitophagy inhibition in PH, exploring the mechanism of HSP90 and Gal3 regulation of mitophagy to promote the development of PH, will lay the foundation for the pathophysiological mechanism of the disease. So, it’s interesting that if regulating the molecules could inhibit the development of PH via suppressing mitophagy.
What is the aim of the project?
Confirm the role of mitophagy inhibition in PH, explore the mechanism of HSP90 and Gal3 regulation of mitophagy to promote the development of PAH.
What techniques and methods are used?
1) Establishment of monocrotaline (MCT) rat PAH model and mouse Hypoxia PAH model. MCT can induce the formation of pulmonary hypertension in rats. a) MCT rat PAH model: Adult SD (Sprague Dawley) rats were given a single intraperitoneal injection of MCT at a dose of 60 mg / kg and developed to PH within 4 weeks. b) mouse Hypoxia PAH model: C57 mice were given subcutaneous injection of SUGEN-5416 (20mg / kg) (once a week) and kept in a hypoxia box (10% O2). Hypoxia for 7 days for 4 weeks. 2) Western blot, Reverse Transcription-Polymerase Chain Reaction (RT-PCR), immunofluorescence to investigate the expression of the target gene in vascular smooth muscle cells. a) Extraction of RNA (Ribonucleic Acid) b) Reverse transcription reaction c) PCR reaction 3) Hsp90 specific inhibitor treatment, treated in two ways: blocking/reversing. 4) PH high pressure evaluation, index determination. There will be a specific machine (powerlab 26T, ADInstruments Shanghai Trading Co., Ltd) to detect the pulmonary artery pressure. 5) The morphology of the cells are observed with Confocal microscope by immunostaining.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
1) Learn how to use western blot, RT-PCT, immunofluorescence and other basic molecular experiments to investigate the expression of the target gene in vascular smooth muscle cells. 2) Learn how to induce a hypoxia model in cells and mice. 3) Learn how to calculate drug concentrations on cells and mice. And how to choose the most suitable concentrations. 4) Learn how to evaluate PH high pressure. 5) Learn about plasmid transfection and adenovirus infection on cells.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Preliminary readings will be provided by the tutor. In addition, the tutor will discuss and explain in detail about the project that students will be conducting. Students are encouraged to take part in the group meeting and seminars.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation - The student will prepare a scientific report - The student’s name will be mentioned in a future publication - The student will have the opportunity to present the results together with the supervisor at a conference
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Cell culture, protein extraction, data analysis
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields - Dental medicine students (IADS members)
- Chen; Feng(#)(*); Li; Xueyi; Aquadro; Emily; Haigh; Stephen; Zhou; Jiliang; Stepp; David W.; Weintraub; Neal L.; Barman; Scott A.; Fulton; David J. R.(*); Inhibition of histone deacetylase reduces transcription of NADPH oxidases and ROS production and ameliorates pulmonary arterial hypertension ; Free Radical Biology and Medicine; 2016.10; 99:167~178
- Barman; Scott A(*); Chen; Feng(*); Li; Xueyi; Haigh; Stephen; Stepp; David W;Kondrikov; Dmitry; Mahboubi; Keyvan; Bordan; Zsuzsanna; Traber; Peter; Su; Yunchao;Fulton; David J R(*); Galectin-3 Promotes Vascular Remodeling and Contributes to PulmonaryHypertension. ; American Journal of Respiratory and Critical CareMedicine; 2018.6.1; 197(11): 1488~1492
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