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Шкурников Максим Юрьевич

Факультет биологии и биотехнологии

Профиль на hse.ru ↗ тел.: + 7 (495) 772-95-90 | 15261
Публикаций
38
Языков
1
Наград
8
Конференций
0
Профиль Публикации (38) Курсы (4)

Профессиональные интересы

молекулярная биологиябиохимиябиоинформатика

Должности

  • Заведующий лабораторией — Факультет биологии и биотехнологии, Лаборатория исследований молекулярных механизмов долголетия
  • Ведущий научный сотрудник — Факультет биологии и биотехнологии, Лаборатория исследований молекулярных механизмов долголетия
  • Профессор — Факультет биологии и биотехнологии, Базовая кафедра Института биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН

Био

  • · Начал работать в НИУ ВШЭ в 2020 году.
  • · Научно-педагогический стаж: 5 лет.

Образование

  • 2024 · Доктор медицинских наук
  • 2009 · Кандидат медицинских наук
  • 2004 · Специалитет: Российский государственный медицинский университет Федерального агентства по здравоохранению и социальному развитию, специальность «Медицинская кибернетика», квалификация «Врач-кибернетик»

Опыт работы

  • · 2004: Август ‒ июнь
  • · 2006: : научный сотрудник, лаборатория ксенотрансплантации, Институт трансплантологии и искусственных органов
  • · 2006: Июль ‒ февраль
  • · 2011: : старший научный сотрудник, лаборатории молекулярной физиологии, Российский научно-исследовательский институт спорта и физического воспитания
  • · 2011: Февраль ‒ Январь
  • · 2014: : ведущий научный сотрудник, лаборатория молекулярной физиологии, Институт общей патологии и патофизиологии РАМН
  • · 2014: Февраль ‒ декабрь
  • · 2017: : старший научный сотрудник, отдел трансляционной онкологии, Московский научно-исследовательский онкологический институт имени П. А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России
  • · 2018: Январь ‒ ноябрь
  • · 2020: : начальник отдела трансляционной онкологии, Московский научно-исследовательский онкологический институт имени П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России
  • · 2020: Декабрь ‒ настоящее время: Факультет биологии и биотехнологии НИУ ВШЭ

Награды и поощрения

  • · Благодарность Министерства науки и высшего образования Российской Федерации (декабрь 2024)
  • · Благодарность проректора НИУ ВШЭ (ноябрь 2024)
  • · Благодарность Факультета биологии и биотехнологии НИУ ВШЭ (февраль 2023)
  • · Надбавка за публикации, вносящие особый вклад в международную научную репутацию НИУ ВШЭ (2022–2025)
  • · Надбавка за публикацию в международном рецензируемом научном издании (2021–2022)
  • · Надбавка за регулярные публикации в международных рецензируемых научных изданиях (2025–2030)
  • · Победитель Конкурса лучших русскоязычных научных и научно-популярных работ работников НИУ ВШЭ – 2024, 2022
  • · Лучший академический руководитель в номинации «Прием иностранных студентов» — 2024

Гранты и проекты

  • — · на соискание учёной степени кандидата наук

Идентификаторы исследователя

Публикации (38)

IGFBP6 regulates extracellular vesicles formation via cholesterol abundance in MDA-MB-231 cells

2024 · ARTICLE · en

Breast cancer recurrence is associated with the growth of disseminated cancer cells that separate from the primary tumor before surgical treatment and hormonal therapy and form a metastatic niche in distant organs. We previously demonstrated that IGFBP6 expression is associated with the risk of early relapse of luminal breast cancer. Knockdown of IGFBP6 in MDA-MB-231 breast cancer cells increased their invasiveness, proliferation, and metastatic potential. In addition, the knockdown of IGFBP6 leads to impaired lipid metabolism. In this study, we demonstrated that the knockdown of the IGFBP6 gene, a highly selective inhibitor of IGF-II, led to a significant decline in the number of secreted extracellular vesicles (EVs) and altered cholesterol metabolism in MDA-MB-231 cells. Knockdown of IGFBP6 led to a decrease in the essential proteins responsible for the biogenesis of cholesterol LDLR and LSS, which reduced the amount by more than 13 times. In addition, the knockdown of IGFBP6 led to a possible change in the profile of adhesion molecules on the surface of EVs. The expression of L1CAM, IGSF3, EpCAM, CD24, and CD44 decreased, and the expression of EGFR increased. We can conclude that the negative prognostic value of low expression of this gene could be associated with increased activity of IGF2 in tumor-associated fibroblasts due to low secretion of IGFBP6 by tumor cells. In addition, changing the profile of adhesion molecules on the surface of tumor EVs may contribute to the more efficient formation of metastatic niches.

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HLA-A*01:01 allele diminishing in COVID-19 patients population associated with non-structural epitope abundance in CD8+ T-cell repertoire

2023 · ARTICLE · en

In mid-2021, the SARS-CoV-2 Delta variant caused the third wave of the COVID-19 pandemic in several countries worldwide. The pivotal studies were aimed at studying changes in the efficiency of neutralizing antibodies to the spike protein. However, much less attention was paid to the T-cell response and the presentation of virus peptides by MHC-I molecules. In this study, we compared the features of the HLA-I genotype in symptomatic patients with COVID-19 in the first and third waves of the pandemic. As a result, we could identify the diminishing of carriers of the HLA-A*01:01 allele in the third wave and demonstrate the unique properties of this allele. Thus, HLA-A*01:01-binding immunoprevalent epitopes are mostly derived from ORF1ab. A set of epitopes from ORF1ab was tested, and their high immunogenicity was confirmed. Moreover, analysis of the results of single-cell phenotyping of T-cells in recovered patients showed that the predominant phenotype in HLA-A*01:01 carriers is central memory T-cells. The predominance of T-lymphocytes of this phenotype may contribute to forming long-term T-cell immunity in carriers of this allele. Our results can be the basis for highly effective vaccines based on ORF1ab peptides.

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Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer

2023 · ARTICLE · en

We developed DCoNA – a statistical tool that allows one to identify pair interactions, which correlation significantly changes between two conditions. Comparing DCoNA with the state-of-the-art analog, we showed that DCoNA is a faster, more accurate, and less memory-consuming tool. We applied DCoNA to prostate mRNA/miRNA-seq data collected from The Cancer Genome Atlas (TCGA) and compared predicted regulatory interactions of miRNA isoforms (isomiRs) and their target mRNAs between normal and cancer samples. As a result, almost all highly expressed isomiRs lost negative correlation with their targets in prostate cancer samples compared to ones without the pathology. One exception to this trend was the canonical isomiR of hsa-miR-93-5p acquiring cancerspecific targets. Further analysis showed that cancer aggresiveness increased with the expression of this isomiR in both TCGA primary tumor samples and 153 blood plasma samples of own patients’ cohort analyzed by miRNA microarrays.

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The signature of SARS-CoV-2 evolution reflects selective pressures within human guts

2023 · ARTICLE · en

In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. In London and Berlin samples represented in GISAID database, we traced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and divided these sequenced in two groups, “Ancestral variants” and “Omicrons,” and analyzed them through the prism of the tissue-specific binding between host miRNAs and viral messenger RNAs. We demonstrate a significant number of miRNA-binding sites in the NSP4 region of the SARS-CoV-2 genome, with evidence of evolutionary pressure within this region exerted by human intestinal miRNAs. Notably, in infected cells, NSP4 promotes the formation of double-membrane vesicles, which serve as the scaffolds for replication-transcriptional complexes and protect viral RNA from intracellular destruction. In 3 years of selection, the loss of many miRNA-binding sites in general and those within the NSP4 in particular has shaped the SARS-CoV-2 genomes. With that, the descendants of the BA.2 variants were promoted as dominant strains, which define current momentum of the pandemics.

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Immunocompetent Mice As a Model for Preclinical Studies of mRNA Vaccine Immunogenicity

2023 · ARTICLE · en

Conducting preclinical studies of mRNA vaccines is complicated by the lack of relevant animal models of the human immune system. Immunocompetent mice are widely used in biomedical research. However, critical differences in the genetics and immune system of mice and humans prevent the study of unique human immune responses in mice. Within the framework of this work, the possibility of modeling the cytotoxic T-cell response to mRNA vaccines encoding the S-protein of the SARS-CoV-2 virus was investigated. High-affinity peptides from S-protein were analyzed for the most frequent allelic variants of human MHC-I, two immunocompetent mouse lines (C57BL/6, BALB/c) and an outbred mouse model of IRC. The results of computer modeling have shown that mouse models can be used in preclinical studies of mRNA vaccines against SARS-CoV-2. Mouse MHC-I is able to present virus peptides that are highly affine for human MHC-I. Moreover, the immunogenicity of some of them has already been confirmed by examining blood samples from patients who have had COVID-19.

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Differences in Presentation of SARS-CoV-2 Omicron Strain Variant BA.1–BA.5 Peptides by HLA Molecules

2022 · ARTICLE · en

In this work, we analyzed the binding affinities of mutated peptides of Omicron strain variants BA.1–BA.5 and the worldwide prevalent HLA alleles. Bioinformatics analysis was conducted with the use of T-CoV web portal. We showed that, for all five viral variants, mutations cause a significant reduction in the number of tightly binding peptides for HLA-B*07:02 and HLA-C*01:02 molecules. At the same time, there were novel potential mutant epitopes (binding affinity less than 50 nM) in case of HLA-A*32:01 allele. Interestingly, mutations caused multidirectional effect on the binding affinities of the viral peptides and HLA-DRB1*03:01. Specifically, Spike protein mutations in the BA.1 variant caused more than 100-fold decrease in PINLVRDLPQGFSAL binding affinity, 10-fold decrease in affinity in the case of BA.2, BA.4, and BA.5 variants, and 30% increase in affinity for the BA.3 variant.

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T-CoV: a comprehensive portal of HLA-peptide interactions affected by SARS-CoV-2 mutations

2022 · ARTICLE · en

Rapidly appearing SARS-CoV-2 mutations can affect T cell epitopes, which can help the virus to evade either CD8 or CD4 T-cell responses. We developed T-cell COVID-19 Atlas (T-CoV, https://t-cov.hse.ru) – the comprehensive web portal, which allows one to analyze how SARS-CoV-2 mutations alter the presentation of viral peptides by HLA molecules. The data are presented for common virus variants and the most frequent HLA class I and class II alleles. Binding affinities of HLA molecules and viral peptides were assessed with accurate in silico methods. The obtained results highlight the importance of taking HLA alleles diversity into account: mutation-mediated alterations in HLA-peptide interactions were highly dependent on HLA alleles. For example, we found that the essential number of peptides tightly bound to HLA-B*07:02 in the reference Wuhan variant ceased to be tight binders for the Indian (Delta) and the UK (Alpha) variants. In summary, we believe that T-CoV will help researchers and clinicians to predict the susceptibility of individuals with different HLA genotypes to infection with variants of SARS-CoV-2 and/or forecast its severity.

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Alterations in SARS-CoV-2 Omicron and Delta peptides presentation by HLA molecules

2022 · ARTICLE · en

The T-cell immune response is a major determinant of effective SARS-CoV-2 clearance. Here, using the recently developed T-CoV bioinformatics pipeline (https://t-cov.hse.ru) we analyzed the peculiarities of the viral peptide presentation for the Omicron, Delta and Wuhan variants of SARS-CoV-2. First, we showed the absence of significant differences in the presentation of SARS-CoV-2-derived peptides by the most frequent HLA class I/II alleles and the corresponding HLA haplotypes. Then, the analysis was limited to the set of peptides originating from the Spike proteins of the considered SARS-CoV-2 variants. The major finding was the destructive effect of the Omicron mutations on PINLVRDLPQGFSAL peptide, which was the only tight binder from the Spike protein for HLA-DRB1*03:01 allele and some associated haplotypes. Specifically, we predicted a dramatical decline in binding affinity of HLA-DRB1*03:01 and this peptide both because of the Omicron BA.1 mutations (N211 deletion, L212I substitution and EPE 212-214 insertion) and the Omicron BA.2 mutations (V213G substitution). The computational prediction was experimentally validated by ELISA with the use of corresponding thioredoxin-fused peptides and recombinant HLA-DR molecules. Another finding was the significant reduction in the number of tightly binding Spike peptides for HLA-B*07:02 HLA class I allele (both for Omicron and Delta variants). Overall, the majority of HLA alleles and haplotypes was not significantly affected by the mutations, suggesting the maintenance of effective T-cell immunity against the Omicron and Delta variants. Finally, we introduced the Omicron variant to T-CoV portal and added the functionality of haplotype-level analysis to it.

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isomiRTar: a comprehensive portal of pan-cancer 5′-isomiR targeting

2022 · ARTICLE · en

Inaccurate cleavage of pri- and pre-miRNA hairpins by Drosha and Dicer results in the generation of miRNA isoforms known as isomiRs. isomiRs with 50 -end variations (50 -isomiRs) create a new dimension in miRNA research since they have different seed regions and distinct targetomes. We developed isomiRTar (https://isomirtar.hse.ru)— a comprehensive portal that allows one to analyze expression profiles and targeting activity of 50 -isomiRs in cancer. Using the Cancer Genome Atlas sequencing data, we compiled the list of 1022 50 -isomiRs expressed in 9282 tumor samples across 31 cancer types. Sequences of these isomiRs were used to predict target genes with miRDB and TargetScan. The putative interactions were then subjected to the co-expression analysis in each cancer type to identify isomiR-target pairs supported by significant negative correlations. Downstream analysis of the data deposited in isomiRTar revealed both cancer-specific and cancer-conserved 50 -isomiR expression landscapes. Pairs of isomiRs differing in one nucleotide shift from 50 -end had poorly overlapping targetomes with the median Jaccard index of 0.06. The analysis of colorectal cancer 50 -isomiR-mediated regulatory networks revealed promising candidate tumor suppressor isomiRs: hsamiR-203a-3p|+1, hsa-miR-192-5p|+1 and hsa-miR-148a-3p|0. In summary, we believe that isomiRTar will help researchers find novel mechanisms of isomiR-mediated gene silencing in different types of cancer

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Immunogenic epitope panel for accurate detection of non-cross-reactive T cell response to SARS-CoV-2

2022 · ARTICLE · en

The ongoing COVID-19 pandemic calls for more effective diagnostic tools. T cell response assessment serves as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, healthy unexposed, and SARS-CoV-2–exposed donors. We identified 75 immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes and described association with more than 1 HLA allele for 14 of these. Exclusion of 2 cross-reactive epitopes that generated a response in prepandemic samples left us with a 73-epitope set that offered excellent diagnostic specificity without losing sensitivity compared with full-length antigens, and this evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic Corona-T-test, which achieved a diagnostic accuracy of 95% in a clinical trial. In a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, we observed a complete absence of T cell response to our epitope panel. In combination with strong reactivity to full-length antigens, this suggests that a cross-reactive response might protect these individuals.

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Курсы (4)