DSA Faculty
API
← к списку преподавателей

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)

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.

DOI ↗ PDF ↗

On the peptide binding affinity changes in population-specific HLA repertoires to the SARS-CoV-2 variants Delta and Omicron

2022 · ARTICLE · en

Objective To investigate the changes of Spike protein-HLA binding affinity profiles between the Wuhan strain and two dominant variants, the Delta and the Omicron strains, among the Taiwanese, the British and the Russian populations. Methods The HLA frequencies and the HLA-peptide binding affinity profiles in the T-CoV database were combined to conduct the study. We focused on the public alleles in the three populations (HLA-A, HLA-B, HLA-C, HLA-DRB1, and/or HLA-DPA1/DPB1 alleles) and the altered peptides of the spike protein (compared to the Wuhan strain) in the Delta G/478K·V1 (B.1.617.2 + AY.1 + AY.2) and the Omicron (BA.1) strains. Results For the Delta strain, tight bindings of the altered peptides to the HLA alleles decrease in all three populations and almost vanish in the Taiwanese population. For the Omicron strain, tight bindings are mostly preserved for both HLA classes and in the Taiwanese and the British populations, with a slight reduction in HLA class II in the Taiwanese (1.4%), while the Russian population preserves a relatively high fraction of tight bindings for both HLA classes. Conclusion We comprehensively reported the changes in the HLA-associated SARS-CoV-2 Spike protein peptide binding profiles among the Taiwanese, the British, and the Russian populations. Further studies are needed to understand the immunological mechanisms and the clinical value of our findings.

DOI ↗ PDF ↗

ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model

2022 · ARTICLE · en

ADGRL1 (latrophilin 1), a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation, and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe ten individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all heterozygous for variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities, while homozygous mice were non-viable. On a permissive background, knockout animals were also born at sub-Mendelian ratios, but many Adgrl1 null mice survived gestation and reached adulthood. Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex, and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological, and behavioral abnormalities in mice and humans.

DOI ↗

A novel approach for a joint analysis of isomiR and mRNA expression data reveals features of isomiR targeting in breast cancer

2022 · ARTICLE · en

A widely used procedure for selecting significant miRNA-mRNA or isomiR-mRNA pairs out of predicted interactions involves calculating the correlation between expression levels of miRNAs/isomiRs and mRNAs in a series of samples. In this manuscript, we aimed to assess the validity of this procedure by comparing isomiR-mRNA correlation profiles in sets of sequence-based predicted target mRNAs and non-target mRNAs (negative controls). Target prediction was carried out using RNA22 and TargetScan algorithms. Spearman’s correlation analysis was conducted using miRNA and mRNA sequencing data of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project. Luminal A, luminal B, basal-like breast cancer subtypes, and adjacent normal tissue samples were analyzed separately. Using the sets of putative targets and non-targets, we introduced adjusted isomiR targeting activity (ITA)—the number of negatively correlated potential isomiR targets adjusted by the background (estimated using non-target mRNAs). We found that for most isomiRs a significant negative correlation between isomiR-mRNA expression levels appeared more often in a set of predicted targets compared to the non-targets. This trend was detected for both classical seed region binding types (8mer, 7mer-m8, 7mer-A1, 6mer) predicted by TargetScan and the non-classical ones (G:U wobbles and up to one mismatch or unpaired nucleotide within seed sequence) predicted by RNA22. Adjusted ITA distributions were similar for target sites located in 3′-UTRs and coding mRNA sequences, while 5′-UTRs had much lower scores. Finally, we observed strong cancer subtype-specific patterns of isomiR activity, highlighting the differences between breast cancer molecular subtypes and normal tissues. Surprisingly, our target prediction- and correlation-based estimates of isomiR activities were practically non-correlated with the average isomiR expression levels neither in cancerous nor in normal samples.

DOI ↗ PDF ↗

HIF Prolyl Hydroxylase Inhibitors for COVID-19 Treatment: Pros and Cons

2021 · ARTICLE · en

The review analyzes the potential advantages and problems associated with using HIF prolyl hydroxylase inhibitors as a treatment for COVID-19. HIF prolyl hydroxylase inhibitors are known to boost endogenous erythropoietin (Epo) and activate erythropoiesis by stabilizing and activating the hypoxia inducible factor (HIF). Recombinant Epo treatment has anti-inflammatory and healing properties, and thus, very likely, will be beneficial for moderate to severe cases of COVID-19. However, HIF PHD inhibition may have a significantly broader effect, in addition to stimulating the endogenous Epo production. The analysis of HIF target genes reveals that some HIF-targets, such as furin, could play a negative role with respect to viral entry. On the other hand, HIF prolyl hydroxylase inhibitors counteract ferroptosis, the process recently implicated in vessel damage during the later stages of COVID-19. Therefore, HIF prolyl hydroxylase inhibitors may serve as a promising treatment of COVID-19 complications, but they are unlikely to aid in the prevention of the initial stages of infection.

DOI ↗ PDF ↗

Extracellular miRNAs and cell-cell communication: problems and prospects

2021 · ARTICLE · en

MicroRNAs (miRNAs) are short RNA molecules regulating multiple cellular processes through posttranscriptional gene silencing. Over the last decade, miRNA have been found in extracellular space and have been consistently shown to mediate functional communication between cells. While it remains widely accepted that miRNA transfer between cells occurs via extracellular vesicles (EVs), multiple other carriers of cell-free miRNA have been described. In addition, some studies have demonstrated that both miRNA and their binding partners, Argonaute proteins, remain hardly detectable in common isolates of EVs. In this work, we summarize the state-of-the-art mechanisms of miRNA sorting and secretion, discuss methodological challenges associated with extracellular miRNA research, and suggest experimental steps to resolve current inconsistencies in the field of miRNA-mediated cell-cell communication.

DOI ↗ PDF ↗

Association of HLA Class I Genotypes With Severity of Coronavirus Disease-19

2021 · ARTICLE · en

Human leukocyte antigen (HLA) class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides at the cell surface where they will be further recognized by T cells. In the present manuscript, we explored whether HLA class I genotypes can be associated with the critical course of Coronavirus Disease-19 by searching possible connections between genotypes of deceased patients and their age at death. HLA-A, HLA-B, and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with next-generation sequencing. Deceased patients were split into two groups according to age at the time of death: n = 26 adult patients aged below 60 and n = 85 elderly patients over 60. With the use of HLA class I genotypes, we developed a risk score (RS) which was associated with the ability to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides by the HLA class I molecule set of an individual. The resulting RS was significantly higher in the group of deceased adults compared to elderly adults [p = 0.00348, area under the receiver operating characteristic curve (AUC ROC = 0.68)]. In particular, presence of HLA-A*01:01 allele was associated with high risk, while HLA-A*02:01 and HLA-A*03:01 mainly contributed to low risk. The analysis of patients with homozygosity strongly highlighted these results: homozygosity by HLA-A*01:01 accompanied early deaths, while only one HLA-A*02:01 homozygote died before 60 years of age. Application of the constructed RS model to an independent Spanish patients cohort (n = 45) revealed that the score was also associated with the severity of the disease. The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19.

DOI ↗ PDF ↗

miRGTF-net: Integrative miRNA-gene-TF network analysis reveals key drivers of breast cancer recurrence

2021 · ARTICLE · en

Analysis of regulatory networks is a powerful framework for identification and quantification of intracellular interactions. We introduce miRGTF-net, a novel tool for construction of miRNA-gene-TF networks. We consider multiple transcriptional and post-transcriptional interaction types, including regulation of gene and miRNA expression by transcription factors, gene silencing by miRNAs, and co-expression of host genes with their intronic miRNAs. The underlying algorithm uses information on experimentally validated interactions as well as integrative miRNA/mRNA expression profiles in a given set of samples. The latter ensures simultaneous tissue-specificity and biological validity of interactions. We applied miRGTF-net to paired miRNA/mRNA-sequencing data of breast cancer samples from The Cancer Genome Atlas (TCGA). Together with topological analysis of the constructed network we showed that considered players can form reliable prognostic gene signatures for ER-positive breast cancer. A number of signatures demonstrated remarkably high accuracy on transcriptomic data obtained by both microarrays and RNA sequencing from several independent patient cohorts. Furthermore, an essential part of prognostic genes were identified as direct targets of transcription factor E2F1. The putative interplay between estrogen receptor alpha and E2F1 was suggested as a potential recurrence factor in patients treated with tamoxifen. Source codes of miRGTF-net are available at GitHub (https://github.com/s-a-nersisyan/miRGTF-net).

DOI ↗ PDF ↗

Hypoxia-Induced miR-148a Downregulation Contributes to Poor Survival in Colorectal Cancer

2021 · ARTICLE · en

Hypoxia is an extensively investigated condition due to its contribution to various pathophysiological processes including cancer progression and metastasis formation. MicroRNAs (miRNAs) are well-known post-transcriptional gene expression regulators. However, their contribution to molecular response to hypoxia is highly dependent on cell/tissue types and causes of hypoxia. One of the most important examples is colorectal cancer, where no consensus on hypoxia-regulated miRNAs has been reached so far. In this work, we applied integrated mRNA and small RNA sequencing, followed by bioinformatics analysis, to study the landscape of hypoxia-induced miRNA and mRNA expression alterations in human colorectal cancer cell lines (HT-29 and Caco-2). A hypoxic microenvironment was chemically modeled using two different treatments: cobalt(II) chloride and oxyquinoline. Only one miRNA, hsa-miR-210-3p, was upregulated in all experimental conditions, while there were nine differentially expressed miRNAs under both treatments within the same cell line. Further bioinformatics analysis revealed a complex hypoxia-induced regulatory network: hypoxic downregulation of hsa-miR-148a-3p led to the upregulation of its two target genes, ITGA5 and PRNP, which was shown to be a factor contributing to tumor progression and poor survival in colorectal cancer patients.

DOI ↗ PDF ↗

Effect of the Expression of ELOVL5 and IGFBP6 Genes on the Metastatic Potential of Breast Cancer Cells

2021 · ARTICLE · en

Breast cancer (BC) is the leading cause of death from malignant neoplasms among women worldwide, and metastatic BC presents the biggest problems for treatment. Previously, it was shown that lower expression of ELOVL5 and IGFBP6 genes is associated with a higher risk of the formation of distant metastases in BC. In this work, we studied the change in phenotypical traits, as well as in the transcriptomic and proteomic profiles of BC cells as a result of the stable knockdown of ELOVL5and IGFBP6 genes. The knockdown of ELOVL5 and IGFBP6 genes was found to lead to a strong increase in the expression of the matrix metalloproteinase (MMP) MMP1. These results were in good agreement with the correlation analysis of gene expression in tumor samples from patients and were additionally confirmed by zymography. The knockdown of ELOVL5 and IGFBP6 genes was also discovered to change the expression of a group of genes involved in the formation of intercellular contacts. In particular, the expression of the CDH11 gene was markedly reduced, which also complies with the correlation analysis. The spheroid formation assay showed that intercellular adhesion decreased as a result of the knockdown of the ELOVL5 and IGFBP6 genes. Thus, the obtained data indicate that malignant breast tumors with reduced expression of the ELOVL5 and IGFBP6 genes can metastasize with a higher probability due to a more efficient invasion of tumor cells.

DOI ↗ PDF ↗

Курсы (6)