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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)

Incautious design of shRNAs for stable overexpression of miRNAs could result in generation of undesired isomiRs

2024 · ARTICLE · en

shRNA-mediated strategy of miRNA overexpression based on RNA Polymerase (Pol III) expression cassettes is widely used for miRNA functional studies. For some miRNAs, e.g., encoded in the genome as a part of a polycistronic miRNA cluster, it is most likely the only way for their individual stable overexpression. Here we have revealed that expression of miRNAs longer than 19 nt (e.g. 23 nt in length hsa-miR-93-5p) using such approach could be accompanied by undesired predominant generation of 5′ end miRNA isoforms (5′-isomiRs). Extra U residues (up to five) added by Pol III at the 3′ end of the transcribed shRNA during transcription termination could cause a shift in the Dicer cleavage position of the shRNA. This results in the formation of 5′-isomiRs, which have a significantly altered seed region compared to the initially encoded canonical hsa-miR-93-5p. We demonstrated that the commonly used qPCR method is insensitive to the formation of 5′-isomiRs and cannot be used to confirm miRNA overexpression. However, the predominant expression of 5′-isomiRs without three or four first nucleotides instead of the canonical isoform could be disclosed based on miRNA-Seq analysis. Moreover, mRNA sequencing data showed that the 5′-isomiRs of hsa-miR-93-5p presumably regulate their own mRNA targets. Thus, omitting miRNA-Seq analysis may lead to erroneous conclusions regarding revealed mRNA targets and possible molecular mechanisms in which studied miRNA is involved. Overall, the presented results show that structures of shRNAs for stable overexpression of miRNAs requires careful design to avoid generation of undesired 5′-isomiRs.

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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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ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis

2023 · ARTICLE · en

Relapse of breast cancer is one of the key obstacles to successful treatment. Previously we have shown that low expression of ELOVL5 and IGFBP6 genes in breast cancer tissue corresponded to poor prognosis. ELOVL5 participates directly in the elongation of polyunsaturated fatty acids (PUFAs) that are considered to play an important role in cancer cell metabolism. Thus, in this work we studied the changes in lipid metabolism in breast cancer cells with reduced expression of either ELOVL5 or IGFBP6 gene.

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Development of a novel mathematical model that explains SARS-CoV-2 infection dynamics in Caco-2 cells

2023 · ARTICLE · en

Mathematical modeling is widely used to study within-host viral dynamics. However, to the best of our knowledge, for the case of SARS-CoV-2 such analyses were mainly conducted with the use of viral load data and for the wild type (WT) variant of the virus. In addition, only few studies analyzed models for in vitro data, which are less noisy and more reproducible. In this work we collected multiple data types for SARS-CoV-2-infected Caco-2 cell lines, including infectious virus titers, measurements of intracellular viral RNA, cell viability data and percentage of infected cells for the WT and Delta variants. We showed that standard models cannot explain some key observations given the absence of cytopathic effect in human cell lines. We propose a novel mathematical model for in vitro SARS-CoV-2 dynamics, which included explicit modeling of intracellular events such as exhaustion of cellular resources required for virus production. The model also explicitly considers innate immune response. The proposed model accurately explained experimental data. Attenuated replication of the Delta variant in Caco-2 cells could be explained by our model on the basis of just two parameters: decreased cell entry rate and increased cytokine production rate.

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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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RNA-binding proteins regulating the CD44 alternative splicing

2023 · ARTICLE · en

Alternative splicing is often deregulated in cancer, and cancer-specific isoform switches are part of the oncogenic transformation of cells. Accumulating evidence indicates that isoforms of the multifunctional cell-surface glycoprotein CD44 play different roles in cancer cells as compared to normal cells. In particular, the shift of CD44 isoforms is required for epithelial to mesenchymal transition (EMT) and is crucial for the maintenance of pluripotency in normal human cells and the acquisition of cancer stem cells (CSC) phenotype for malignant cells. The growing and seemingly promising use of splicing inhibitors for treating cancer and other pathologies gives hope for the prospect of using such an approach to regulate CD44 alternative splicing. This review integrates current knowledge about regulating CD44 alternative splicing by RNA-binding proteins.

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Challenges in Characterization of Transcriptomes of Extracellular Vesicles and Non-Vesicular Extracellular RNA Carriers

2023 · ARTICLE · en

Since its original discovery over a decade ago, extracellular RNA (exRNA) has been found in all biological fluids. Furthermore, extracellular microRNA has been shown to be involved in communication between various cell types. Importantly, the exRNA is protected from RNases degradation by certain carriers including membrane vesicles and non-vesicular protein nanoparticles. Each type of carrier has its unique exRNA profile, which may vary depending on cell type and physiological conditions. To clarify putative mechanisms of intercellular communication mediated by exRNA, the RNA profile of each carrier has to be characterized. While current methods of biofluids fractionation are continuously improving, they fail to completely separate exRNA carriers. Likewise, most popular library preparation approaches for RNA sequencing do not allow obtaining exhaustive and unbiased data on exRNA transcriptome. In this mini review we discuss ongoing progress in the field of exRNA, with the focus on exRNA carriers, analyze the key methodological challenges and provide recommendations on how the latter could be overcome.

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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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Модуляторы сигнального пути Nrf2 усиливают цитотоксический эффект стандартных химиотерапевтических препаратов на органоиды метастатического колоректального рака

2023 · ARTICLE · ru

Исследована активность известных модуляторов сигнального пути Nrf2 (бардоксолон и брусатол) на ранее полученных от трёх пациентов культурах опухолевых органоидов метастатического колоректального рака. Действие модуляторов было изучено как в виде монотерапии, так и в комбинации со стандартными химиотерапевтическими препаратами, применяющимися для лечения колоректального рака. Ингибитор Nrf2 брусатол и активатор Nrf2 бардоксолон обладают противоопухолевой активностью. Более того, бардоксолон и брусатол также значительно усиливают действие химиотерапевтических препаратов 5-фторурацила, оксалиплатина и метаболита иринотекана SN-38. Таким образом, бардоксолон и брусатол можно считать перспективными кандидатами для дальнейших доклинических и клинических исследований по терапии колоректального рака.

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Курсы (6)