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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)

Hairpin sequence and structure is associated with features of isomiR biogenesis

2021 · ARTICLE · en

MiRNA isoforms (isomiRs) are single stranded small RNAs originating from the same pri-miRNA hairpin as a result of cleavage by Drosha and Dicer enzymes. Variations at the 5ʹ-end of a miRNA alter the seed region of the molecule, thus affecting the targetome of the miRNA. In this manuscript, we analysed the distribution of miRNA cleavage positions across 31 different cancers using miRNA sequencing data of TCGA project. As a result, we found that the processing positions are not tissue specific and that all miRNAs could be correctly classified as ones exhibiting homogeneous or heterogeneous cleavage at one of the four cleavage sites. In 42% of cases (42 out of 100 miRNAs), we observed imprecise 5ʹ-end Dicer cleavage, while this fraction was only 14% for Drosha (14 out of 99). To the contrary, almost all cleavage sites of 3ʹ-ends (either Drosha or Dicer) were heterogeneous. With the use of only four nucleotides surrounding a 5ʹ-end Dicer cleavage position we built a model which allowed us to distinguish between homogeneous and heterogeneous cleavage with the reliable quality (ROC AUC = 0.68). Finally, we showed the possible applications of the study by the analysis of two 5ʹ-end isoforms originating from the same exogeneous shRNA hairpin. It turned out that the less expressed shRNA variant was functionally active, which led to the increased off-targeting. Thus, the obtained results could be applied to the design of shRNAs whose processing will result in a single 5ʹ-variant.

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Chemical Induction of Trophoblast Hypoxia by Cobalt Chloride Leads to Increased Expression of DDIT3

2021 · ARTICLE · en

Choriocarcinoma cells BeWo b30 are used to model human placental trophoblast hypoxia using cobalt (II) chloride and hydroxyquinoline derivative (HD) as chemical inducers of hypoxia-inducible factor (HIF). In this study, it was shown that both substances activate the hypoxic pathway and the epithelial–mesenchymal transition and inhibit the pathways of cell proliferation. However, CoCl2 caused activation of the apoptosis pathway, increased the activity of effector caspases 3 and 7, and increased the expression of the unfolded protein response target DDIT3. The mTORC1 pathway was activated upon exposition to CoCl2, while HD suppressed this pathway, as it happens during real trophoblast hypoxia. Thus, effect of CoCl2 on BeWo cells can be a model of severe hypoxia with activation of apoptosis, while HD mimics moderate hypoxia.

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Endocytosis and Transcytosis of SARS-CoV-2 Across the Intestinal Epithelium and Other Tissue Barriers

2021 · ARTICLE · en

Since 2003, the world has been confronted with three new betacoronaviruses that cause human respiratory infections: SARS-CoV, which causes severe acute respiratory syndrome (SARS), MERS-CoV, which causes Middle East respiratory syndrome (MERS), and SARS-CoV-2, which causes Coronavirus Disease 2019 (COVID-19). The mechanisms of coronavirus transmission and dissemination in the human body determine the diagnostic and therapeutic strategies. An important problem is the possibility that viral particles overcome tissue barriers such as the intestine, respiratory tract, blood-brain barrier, and placenta. In this work, we will 1) consider the issue of endocytosis and the possibility of transcytosis and paracellular trafficking of coronaviruses across tissue barriers with an emphasis on the intestinal epithelium; 2) discuss the possibility of antibody-mediated transcytosis of opsonized viruses due to complexes of immunoglobulins with their receptors; 3) assess the possibility of the virus transfer into extracellular vesicles during intracellular transport; and 4) describe the clinical significance of these processes. Models of the intestinal epithelium and other barrier tissues for in vitro transcytosis studies will also be briefly characterized.

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Fra-2 overexpression upregulates pro-metastatic cell-adhesion molecules, promotes pulmonary metastasis, and reduces survival in a spontaneous xenograft model of human breast cancer

2021 · ARTICLE · en

Purpose: The transcription factor Fra-2 affects the invasive potential of breast cancer cells by dysregulating adhesion molecules in vitro. Previous results suggested that it upregulates the expression of E- and P-selectin ligands. Such selectin ligands are important members of the leukocyte adhesion cascade, which govern the adhesion and transmigration of cancer cells into the stroma of the host organ of metastasis. As so far, no in vivo data are available, this study was designed to elucidate the role of Fra-2 expression in a spontaneous breast cancer metastasis xenograft model. Methods: The effect of Fra-2 overexpression in two stable Fra-2 overexpressing clones of the human breast cancer cell line MDA MB231 on survival and metastatic load was studied after subcutaneous injection into scid and E- and P-selectin deficient scid mice. Results: Fra-2 overexpression lead to a significantly shorter overall survival and a higher amount of spontaneous lung metastases not only in scid mice, but also in E- and P-deficient mice, indicating that it regulates not only selectin ligands, but also selectin-independent adhesion processes. Conclusion: Thus, Fra-2 expression influences the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells in a breast cancer xenograft model.

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An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation

2021 · ARTICLE · en

Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro.

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ECM–Receptor Regulatory Network and Its Prognostic Role in Colorectal Cancer

2021 · ARTICLE · en

Interactions of the extracellular matrix (ECM) and cellular receptors constitute one of the crucial pathways involved in colorectal cancer progression and metastasis. With the use of bioinformatics analysis, we comprehensively evaluated the prognostic information concentrated in the genes from this pathway. First, we constructed a ECM–receptor regulatory network by integrating the transcription factor (TF) and 5’-isomiR interaction databases with mRNA/miRNA-seq data from The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD). Notably, one-third of interactions mediated by 5’-isomiRs was represented by noncanonical isomiRs (isomiRs, whose 5’-end sequence did not match with the canonical miRBase version). Then, exhaustive search-based feature selection was used to fit prognostic signatures composed of nodes from the network for overall survival prediction. Two reliable prognostic signatures were identified and validated on the independent The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) cohort. The first signature was made up by six genes, directly involved in ECM–receptor interaction: AGRN, DAG1, FN1, ITGA5, THBS3, and TNC (concordance index 0.61, logrank test p = 0.0164, 3-years ROC AUC = 0.68). The second hybrid signature was composed of three regulators: hsa-miR-32-5p, NR1H2, and SNAI1 (concordance index 0.64, logrank test p = 0.0229, 3-years ROC AUC = 0.71). While hsa-miR-32-5p exclusively regulated ECM-related genes (COL1A2 and ITGA5), NR1H2 and SNAI1 also targeted other pathways (adhesion, cell cycle, and cell division). Concordant distributions of the respective risk scores across four stages of colorectal cancer and adjacent normal mucosa additionally confirmed reliability of the models.

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9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

2021 · ARTICLE · en

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

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A post-processing algorithm for miRNA microarray data

2020 · ARTICLE · en

One of the main disadvantages of using DNA microarrays for miRNA expression profiling is the inability of adequate comparison of expression values across different miRNAs. This leads to a large amount of miRNAs with high scores which are actually not expressed in examined samples, i.e., false positives. We propose a post-processing algorithm which performs scoring of miRNAs in the results of microarray analysis based on expression values, time of discovery of miRNA, and correlation level between the expressions of miRNA and corresponding pre-miRNA in considered samples. The algorithm was successfully validated by the comparison of the results of its application to miRNA microarray breast tumor samples with publicly available miRNA-seq breast tumor data. Additionally, we obtained possible reasons why miRNA can appear as a false positive in microarray study using paired miRNA sequencing and array data. The use of DNA microarrays for estimating miRNA expression profile is limited by several factors. One of them consists of problems with comparing expression values of different miRNAs. In this work, we show that situation can be significantly improved if some additional information is taken into consideration in a comparison.

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Knockdown of the α5 Laminin Chain Affects Differentiation of Colorectal Cancer Cells and Their Sensitivity to Chemotherapy

2020 · ARTICLE · en

The interaction of tumor cells with the extracellular matrix (ECM) may affect the rate of cancer progression and metastasis. One of the major components of ECM are laminins, the heterotrimeric glycoproteins consisting of α-, β-, and γ-chains (αβγ). Laminins interact with their cell surface receptors and, thus, regulate multiple cellular processes. In this work, we demonstrate that shRNA-mediated knockdown of the α5 laminin chain results in Wnt- and mTORC1-dependent partial dedifferentiation of colorectal cancer cells. Furthermore, we showed that this dedifferentiation involved activation of ER-stress signaling, pathway promoting the sensitivity of cells to 5-fluorouracil.

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Integrative analysis of miRNA and mRNA sequencing data reveals potential regulatory mechanisms of ACE2 and TMPRSS2

2020 · ARTICLE · en

Development of novel approaches for regulating the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) is becoming increasingly important within the context of the ongoing COVID-19 pandemic since these enzymes play a crucial role in cell infection. In this work we searched for putative ACE2 and TMPRSS2 expression regulation networks mediated by various miRNA isoforms (isomiR) across different human organs using publicly available paired miRNA/mRNA-sequencing data from The Cancer Genome Atlas (TCGA) project. As a result, we identified several miRNA families targeting ACE2 and TMPRSS2 genes in multiple tissues. In particular, we found that lysine-specific demethylase 5B (JARID1B), encoded by the KDM5B gene, can indirectly affect ACE2 / TMPRSS2 expression by repressing transcription of hsa-let-7e / hsa-mir-125a and hsa-mir-141 / hsa-miR-200 miRNA families which are targeting these genes.

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Курсы (6)