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Тоневицкий Александр Григорьевич

Факультет биологии и биотехнологии

Профиль на hse.ru ↗ тел.: +7 (495) 772-95-90 | 15093
Публикаций
92
Языков
1
Наград
8
Конференций
1
Профиль Публикации (92) Курсы (6)

Профессиональные интересы

молекулярная биологиямикрофлюидные системыбелковые молекулы

Должности

  • Декан — Факультет биологии и биотехнологии
  • Профессор — Факультет биологии и биотехнологии, Базовая кафедра Института биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН
  • Главный научный сотрудник — Факультет биологии и биотехнологии, Лаборатория исследований молекулярных механизмов долголетия
  • Главный научный сотрудник — Факультет биологии и биотехнологии, Международная лаборатория микрофизиологических систем

Био

  • · Начал работать в НИУ ВШЭ в 2018 году.
  • · Научно-педагогический стаж: 18 лет.

Образование

  • 2025 · Академик РАН
  • 2006 · Член-корреспондент РАН
  • 1995 · Ученое звание: Профессор
  • 1993 · Доктор биологических наук
  • 1985 · Кандидат биологических наук
  • 1979 · Специалитет: Московский государственный университет им. М.В. Ломоносова, специальность «Биология», квалификация «Биолог»

Опыт работы

  • · 1974-1981: Российский кардиологический центр РКНПК МЗ РФ
  • · 1994: Присвоено звание профессора по специальности «Молекулярная биология»
  • · 1991-1995: Заведующий лабораторией в «Государственный НИИ генетики»
  • · 1995-1996: Заместитель директора Института иммунологии МЗ и МПРФ
  • · 1996-2006: Заместитель директора НИИ Трансплантологии и искусственных органов МЗ РФ
  • · 2006: Избран членом-корреспондентом Российской Академии Наук
  • · 2006-2011: Директор ФГУ «Всероссийский научно-исследовательский институт физической культуры и спорта» Министерства спорта, туризма и молодежной политики Российской Федерации
  • · 2011-2014: Заведующий лабораторией НИИ общей патологии и патофизиологии РАМН
  • · 2014-2017: Заведующий отделом трансляционной онкологии ФГБУ «НМИРЦ» Минздрава России
  • · 2017-2018: Ведущий научный сотрудник лаборатории биокатализа ФГБУН Институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наук (ИБХ РАН)
  • · 2018: с Заведующий кафедры клеточной биологии ФГАОУ ВО Национального исследовательского университета «Высшая школа экономики»
  • · Другие занимаемые должности
  • · Председатель экспертной комиссии по биологии и наукам о жизни Совета по грантам Президента РФ Министерства образования и науки РФ;
  • · Член экспертного совета по биотехнологии Министерства промышленности и торговли РФ;
  • · Заместитель председателя экспертного совета РФФИ по международным грантам.

Награды и поощрения

  • · Орден Дружбы народов (сентябрь 2024)
  • · Почетная грамота НИУ ВШЭ (март 2022)
  • · Благодарность Высшей школы экономики (декабрь 2021)
  • · Почетное звание "Заслуженный деятель науки Российской Федерации" (июнь 2018)
  • · Почетная грамота Российской Академии медицинских наук (июнь 2012)
  • · Надбавка за публикацию в журнале из Списка А (и приравненном к нему научном издании) (2024–2025, 2023–2024)
  • · Надбавка за публикацию в международном рецензируемом научном издании (2022–2023, 2021–2022, 2019–2021)
  • · Надбавка за регулярные публикации в международных рецензируемых научных изданиях (2025–2030)

Гранты и проекты

  • — · на соискание учёной степени кандидата наук

Конференции (1)

Показать все
  • · 2024: Седьмой онлайн-семинар по математическому моделированию в области иммунологии (Москва). Доклад: Моделирование динамики SARS-CoV-2 в клеточных линиях

Идентификаторы исследователя

Публикации (92)

Assessing the Efficacy of Anti-Cancer Drugs on Organoid Models Derived from Prostate Cancer

2023 · ARTICLE · en

Доказано, что опухолевые органоиды хорошо отражают фенотипические и генетические характеристики исходного биоматериала. Сообщалось, что результаты тестирования лекарственных препаратов на органоидных культурах могут передавать клинический ответ пациентов. В данной работе из биопсийного материала рака предстательной железы (РПЖ) была получена органоидная культура, на которой были протестированы препараты доцетаксел и энзалутамид, применяющиеся в клинической практике для лечения РПЖ. Было проведено сравнение разных способов оценки эффективности препаратов in vitro. Было показано, что полуингибирующая концентрация доцетаксела была значительно ниже, чем у энзалутамида. Однако, при проведении эксперимента с клинически значимыми концентрациями и временами инкубации, энзалутамид демонстрировал более высокую эффективность, чем доцетаксел. Таким образом, для дальнейшего применения в клинической практике, важно оптимизировать условия тестирования препаратов на культурах in vitro.

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Metabolic effects of vasopressin in pathophysiology of diabetic kidney disease

2023 · ARTICLE · en

The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.

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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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Low expression of CD24 is associated with poor survival in colorectal cancer

2022 · ARTICLE · en

In this study we analyzed expression of CD24 in a cohort of colorectal cancer patients using immunohistochemistry staining of CD24. We found a significant association between absence or low expression of CD24 (10% of membranous and 55% of cytoplasmic staining) and shortened patient survival. Protein localization played a crucial role in the prognosis: membranous form was the major and prognostic one in primary tumors, while cytoplasmic expression was elevated in liver metastases compared to the primary tumors and contained prognostic information. Then, using The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) RNA-seq data, we showed that CD24 mRNA level was two-fold decreased in primary colorectal cancers compared to adjacent normal mucosa. Like the protein staining data, ten percent of patients with the lowest mRNA expression levels of CD24 in primary tumors had reduced survival compared to the ones with higher expression. To explain these findings mechanistically, shRNA-mediated CD24 knockdown was performed in HT-29 colorectal cancer cells. It resulted in the increase of cell migration in vitro, no changes in proliferation and apoptosis, and a slight decrease in cell invasion. As increased cell migration is a hallmark of metastasis formation, this finding corroborates the association of a decreased CD24 expression with poor prognosis. Differential gene expression analysis revealed upregulation of genes involved in cell migration in the group of patients with low CD24 expression, including integrin subunit α3 and α3, β3 subunits of laminin 332. Further co-expression analysis identified SPI1, STAT1 and IRF1 transcription factors as putative master-regulators in this group.

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ExhauFS: exhaustive search-based feature selection for classification and survival regression

2022 · ARTICLE · en

Feature selection is one of the main techniques used to prevent overfitting in machine learning applications. The most straightforward approach for feature selection is an exhaustive search: one can go over all possible feature combinations and pick up the model with the highest accuracy. This method together with its optimizations were actively used in biomedical research, however, publicly available implementation is missing. We present ExhauFS—the user-friendly command-line implementation of the exhaustive search approach for classification and survival regression. Aside from tool description, we included three application examples in the manuscript to comprehensively review the implemented functionality. First, we executed ExhauFS on a toy cervical cancer dataset to illustrate basic concepts. Then, multi-cohort microarray breast cancer datasets were used to construct gene signatures for 5-year recurrence classification. The vast majority of signatures constructed by ExhauFS passed 0.65 threshold of sensitivity and specificity on all datasets, including the validation one. Moreover, a number of gene signatures demonstrated reliable performance on independent RNA-seq dataset without any coefficient re-tuning, i.e., turned out to be cross-platform. Finally, Cox survival regression models were used to fit isomiR signatures for overall survival prediction for patients with colorectal cancer. Similarly to the previous example, the major part of models passed the pre-defined concordance index threshold 0.65 on all datasets. In both real-world scenarios (breast and colorectal cancer datasets), ExhauFS was benchmarked against state-of-the-art feature selection models, including L1-regularized sparse models. In case of breast cancer, we were unable to construct reliable cross-platform classifiers using alternative feature selection approaches. In case of colorectal cancer not a single model passed the same 0.65 threshold. Source codes and documentation of ExhauFS are available on GitHub: https://github.com/s-a-nersisyan/ExhauFS.

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Differences in medium-induced conformational plasticity presumably underlie different cytotoxic activity of ricin and viscumin

2022 · ARTICLE · en

Structurally similar catalytic subunits A of ricin (RTA) and viscumin (MLA) exhibit cytotoxic activity through ribosome inactivation. Ricin is more cytotoxic than viscumin, although the molecular cause of this is still poorly understood. To shed more light on this problem, we used a combined biochemical / molecular modeling approach to assess the possible relationship between the activity of toxins and their structural/dynamic properties. Based on bioassay measurements, it was suggested that the differences in activity are associated with the ability of RTA and MLA to undergo structural/hydrophobic rearrangements when trafficking through the endoplasmic reticulum (ER) membrane. Molecular dynamics simulations and surface hydrophobicity mapping of both proteins in different media showed that RTA rearranges its structure in a membrane-like environment much more efficiently than MLA. The hydrophobic organization of their refolded states is also drastically different. We assume that the higher conformational plasticity of RTA is favorable for the ER-mediated translocation pathway, which leads to a higher rate of the toxin penetration into the cytoplasm.

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Specificity of viscumin revised. As probed with a printed glycan array

2022 · ARTICLE · en

Viscumin, a lectin used in anti-cancer therapy, was originally considered as βGal recognizing protein; later, an ability to bind 6'-sialyl N-acetyllactosamine (6'SLN) terminated gangliosides was found. Here we probed viscumin with a printed glycan array (PGA) containing a large number of mammalian sulfated glycans, and found a strong binding to glycans with 6-O-SuGal moiety as lactose, N-acetyllactosamine (LN), di-N-acetyllactosamine (LacdiNAc), and even 6-O-SuGalNAcα (but not SiaTn). Also, the ability to bind some of αGal terminated glycans, including Gala1-3Galb1-4GlcNAc, was observed. Unexpectedly, only weak interaction was detected with parent neutral β-galactosides including LN-LN-LN and branched (LN)2LN oligolactosamines; in the light of these data, one should not confidently classify viscumin as a β-galactoside-binding lectin. Carrying out PGA in the presence of neutral or sulfated/sialylated glycan, together with sequential elution from lactose-sepharose and consideration of the protein structure, lead to the conclusion that two glycan-binding sites of viscumin have different specificities, one of which prefers charged sulfated and sialylatedmoieties.

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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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Курсы (6)