INFORMATION ABOUT PROJECT,
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COMMON PART

Project Number23-25-00477

Project titleMolecular genetic biomarkers of cerebral atherosclerosis progression

Project LeadTanashyan Marine

AffiliationResearch Center of Neurology,

Research area 05 - FUNDAMENTAL RESEARCH IN MEDICINE, 05-219 - Clinical neurology

KeywordsmicroRNA, atherosclerosis, exosomes, ischemic stroke, cerebrovascular pathology

PROJECT CONTENT

Annotation
Atherosclerosis is a multifactorial disease that affects almost all vascular systems of the human body. Atherosclerosis in the cerebral vessels is one of the leading causes of ischemic stroke (in up to 50% of cases according to the literature [J.-W. Chung et al., 2014]). The pathogenesis of atherosclerosis involves chronic inflammation, metabolic and lipid accumulation disorders, oxidative stress, immune pathology, numerous non-hereditary risk factors (environmental pollution, smoking, dietary preferences and lifestyle), as well as epigenetic regulation, in particular, microRNA. MicroRNAs are small (about 22 nucleotides), single-strand, non-coding RNA sequences that appear to influence most (if not all) biological processes. They act as significant post-transcriptional modulators / regulators of gene expression. Typically, miRNAs suppress gene expression by interacting with the 3 'untranslated region of the target messenger RNA (mRNA), causing it to degrade or blocking translation of the gene product. One microRNA can modulate many mRNAs involved in various biological processes; at the same time, one mRNA can be regulated by several microRNAs. MicroRNAs are involved (to one degree or another) in almost all molecular links in the pathogenesis of atherosclerosis, including endothelial function, impaired cholesterol metabolism, activation of monocytes and their invasion of the vascular wall, activation of platelets and smooth muscle cells of the endothelium, and plaque formation. Diagnosis of cerebral atherosclerosis is based on the available ultrasound technique (in particular, duplex scanning of brachiocephalic, i.e. carotid and vertebral, arteries), however, the idea of the risk of progression of this disease (with an increase in the size of atherosclerotic plaque and / or its destabilization with the development of ischemic stroke) remain the prerogative of scientific research and, as such, have not been introduced into routine practice. Existing methods of stroke prevention in patients with cerebral atherosclerosis include the use of antiplatelet drugs (for example, aspirin) and lipid-lowering drugs (in particular, statins), as well as the use of angiosurgical interventions with a high degree of stenosis. Despite this, the percentage of ischemic strokes remains high, both in the Russian population and in the world, which necessitates the search for new biomarkers of cerebral atherosclerosis, primarily in order to select patients who need more "aggressive" therapeutic tactics. In the proposed project, the main focus is on determining the leukocyte and exosomal expression of a number of microRNAs, which, according to the literature, are associated with various links of atherogenesis (in particular, in the carotid artery system). Thus, it is planned to analyze the following microRNAs: miR-126- (3p / 5p), miR-29a- (3p / 5p), miR-33a- (3p / 5p), miR-21- (3p / 5p), miR-532 - (3p / 5p), miR-200c- (3p / 5p), miR-186- (3p / 5p), miR-100- (3p / 5p), miR-146a- (3p / 5p), miR-155 - (3p / 5p), miR-216a- (3p / 5p), miR-374- (3p / 5p), miR-183- (3p / 5p), miR-106b- (3p / 5p), miR-712 - (3p / 5p), miR-329- (3p / 5p), miR-494- (3p / 5p) - at different “stages” of atherosclerosis development. This is reflected in the design of the study, where all patients were divided into 3 main groups: a control group (without signs of carotid atherosclerosis), patients with "asymptomatic" carotid stenosis (narrowing of the carotid artery by 50% or more without indications of previous strokes ) and a group of patients in the late period after an ischemic stroke (atherothrombotic subtype). It seems to us that this approach will allow the most complete disclosure of the role of microRNAs in the development of cerebral atherosclerosis and potentially identifying the most significant proatherogenic and antiatherogenic biomarkers. The data obtained in the course of the study on the relationships between the expression of a number of genes and miRNAs will be of both fundamental importance (elucidating the role of miRNA regulation in atherogenesis) and a promising clinical application, especially concerning the use of miRNAs as biomarkers of cerebral atherosclerosis, as well as as a potential use for targeted correction of this pathology. The claimed research is in the trend of modern works devoted to microRNAs. It also seems important to us to note that in most of the articles available to us, one or two microRNAs are analyzed in small samples, which does not always allow us to draw a conclusion about significant clinical correlations. At the same time, we propose a project in which, on a relatively large sample, a sufficient amount of microRNAs (which is fundamentally both leukocyte and exosomal expression) will be simultaneously investigated, which may make it possible to obtain a more substantiated picture of the participation of these molecules in the regulation of pathological links of cerebral atherosclerosis.

Expected results
In the course of the proposed project, it is proposed for the first time in the Russian Federation on a cohort of patients with cerebral (carotid) atherosclerosis to evaluate the exosomal and leukocyte expression of the microRNA panel, which, according to the literature and our own data, is associated with atherogenesis, as well as to identify a number of potentially pro-atherogenic and antiatherogenic biomarkers. Considering the proposed set of microRNAs, the studied pathology (cerebral atherosclerosis) and the absence of studies in the world that are similar in number and composition of analyzed indicators in the available sources, the expected results are of global priority. The results obtained will make it possible to isolate a number of biomarkers of carotid atherosclerosis for the purpose of their use in clinical practice - moreover, the significance of the data obtained will justify the introduction of methods for the isolation and analysis of microRNA into wider practice. The latter is an important stage on the way to personalized medicine, which is one of the priority strategies of scientific and technological development in the Russian Federation.

REPORTS