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Study of the role of Clonal Hematopoiesis in the calcific Aortic Valve Disease
Universita degli Studi di Ferrara
Department of Morphology, Surgery and Experimental Biology, Via Fossato di Mortara 64/B 44121 Ferrara, Italy
Type of Research Project
- Basic science
What is the background of the project?
Calcific aortic valve disease (CAVD) can be asymptomatic (aortic sclerosis) or it can lead to remodeling of valve tissue sufficiently severe to result in hemodynamic changes at the aortic valve (aortic stenosis, AS). Echocardiography helps to make the diagnosis of CAVD but is not able to predict its evolution and therefore is unable to give the opportunity to intervene at the early stages of the disease [Small et al., ATVB 2017]. Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer and cardiovascular diseases such as myocardial infarction and atherosclerosis [Jaiswal et al., NEJM, 2017]. It is not known if CHIP is also involved in CAVD pathogenesis which shares many similarities with the process of atherosclerosis. Our hypothesis is that patients with aortic stenosis have higher frequency of somatic mutations in hematopoietic cells, in comparison with age and CV risk matched control, which could be a marker of the pathology. By stratifying CAVD patients according to CHIP mutation we could identify those at high risk of developing calcific aortic valve stenosis.
What is the aim of the project?
The main purpose of this study is to assess whether CHIP is related to an increase in the incidence and severity of AS. In a second phase, after establishing a correlation between CHIP and AS, the molecular mechanism by which somatic blood-cell mutated clones favor the development of the disease will be investigated.
What techniques and methods are used?
This is a case-control retrospective study investigating the difference in frequency of CHIP between a group of patients with AS subjected to aortic valve replacement (AVR) - either surgical or by transcatheter aortic valve implantation (TAVI)-and an age, CV risk- matched group without AS. The research objectives will be addressed by analyzing the presence of mutated clones in the blood samples of control and cases. Since polymorphisms in LpA gene and mutations in Notch1 gene have been associated to increased risk of AS, we will characterize these genotypes in both cohorts. This part of the study will require DNA extraction from blood cells, sequencing of the CHIP genes and data analysis, in collaboration with bioinformatics, to identify CHIP carriers. In a second phase, the mechanism of the putative role of CHIP in AS will be investigated in the subgroup of patients subjected to surgical aortic valve replacement by analyzing RNA isolated from biopsies of the valve samples collected during surgery (qRT-PCR-quantitative Reverse Transcription Polymerase Chain Reaction) and changes in circulating proteins (ELISA-Enzyme-Linked ImmunoSorbent Assay). Cellular model of the disease (aortic valve interstitial cells) and inflammation-related cells (macrophages) will be used to verify hypothesis based on the analyses of patients samples.
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
- If the project includes “lab work”
- the student will take active part in the practical aspect of the project
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will be involved in the design,conduction and analysis of the experiment. He/she is expected, after a training, to conduct small experimental tasks (cell counting, seeding and observation under the microscope, DNA /RNA extraction and tissue staining). The student is also expected to keep up with the literature relevant for the project. The student’s name will be mentioned in a future publication if the performance in these tasks will be excellent.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The tutor will provide a list of pubblications containing the background and the rationale of the study.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student’s name will be mentioned in a future publication - No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic knowledge of cellular and molecular biology
Are there any legal limitations in the student’s involvement
For safety regulations, the student can be in the laboratory only when the laboratory personnel is also present.
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system
- Jaiswal S; Ebert BL. Clonal hematopoiesis in human aging and disease. Science 2019; 366 eaan4673
- Jaiswal S; Natarajan P; Silver AJ; et al. Clonal Hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017; 377: 111-21. doi:10.1056/NEJMoa1701719
- Libby P; Sidlow R; Lin AE; et al. Clonal Hematopoiesis: Crossroads of Aging; Cardiovascular Disease; and Cancer: JACC Review Topic of the Week. J Am Coll Cardiol 2019; 74: 567-77. doi: 10.1016/j.jacc.2019.06.007
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