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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)

Impedance Spectroscopy as a Tool for Monitoring Performance in 3D Models of Epithelial Tissues

2019 · ARTICLE · en

In contrast to traditional 2D cell cultures, both 3D models and organ-on-a-chip devices allow the study of the physiological responses of human cells. These models reconstruct human tissues in conditions closely resembling the body. Translation of these techniques into practice is hindered by associated labor costs, a need which may be remedied by automation. Impedance spectroscopy (IS) is a promising, automation-compatible label-free technology allowing to carry out a wide range of measurements both in real-time and as endpoints. IS has been applied to both the barrier cultures and the 3D constructs. Here we provide an overview of the impedance-based analysis in different setups and discuss its utility for organ-on-a-chip devices. Most attractive features of impedance-based assays are their compatibility with high-throughput format and supports for the measurements in real time with high temporal resolution, which allow tracing of the kinetics. As of now, IS-based techniques are not free of limitations, including imperfect understanding of the parameters that have their effects on the impedance, especially in 3D cell models, and relatively high cost of the consumables. Moreover, as the theory of IS stems from electromagnetic theory and is quite complex, work on popularization and explanation of the method for experimental biologists is required. It is expected that overcoming these limitations will lead to eventual establishing IS based systems as a standard for automated management of cell-based experiments in both academic and industry environments.

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LAMA4-Regulating miR-4274 and Its Host Gene SORCS2 Play a Role in IGFBP6-Dependent Effects on Phenotype of Basal-Like Breast Cancer

2019 · ARTICLE · en

Specificity of RNAi to selected target is challenged by off-target effects, both canonical and non-canonical. Notably, more than half of all human microRNAs are co-expressed with hosting them proteincoding genes. Here we dissect regulatory subnetwork centered on IGFBP6 gene, which is associated with low proliferative state and high migratory activity of basal-like breast cancer. We inhibited expression of IGFBP6 gene in a model cell line for basal-like breast carcinoma MDA-MB-231, then traced secondary and tertiary effects of this knockdown to LAMA4, a laminin encoding gene that contributes to the phenotype of triple-negative breast cancer. LAMA4-regulating miRNA miR-4274 and its host gene SORCS2 were highlighted as intermediate regulators of the expression levels of LAMA4, which correlated in a basal-like breast carcinoma sample subset of TCGA to the levels of SORCS2 negatively. Overall, our study points that the secondary and tertiary layers of regulatory interactions are certainly underappreciated. As these types of molecular event may significantly contribute to the formation of the cell phenotypes after RNA interference based knockdowns, further studies of multilayered molecular networks affected by RNAi are warranted.

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LAMA4-Regulating miR-4274 and Its Host Gene SORCS2 Play a Role in IGFBP6-Dependent Effects on Phenotype of Basal-Like Breast Cancer

2019 · ARTICLE · en

Specificity of RNAi to selected target is challenged by off-target effects, both canonical and non-canonical. Notably, more than half of all human microRNAs are co-expressed with hosting them proteincoding genes. Here we dissect regulatory subnetwork centered on IGFBP6 gene, which is associated with low proliferative state and high migratory activity of basal-like breast cancer. We inhibited expression of IGFBP6 gene in a model cell line for basal-like breast carcinoma MDA-MB-231, then traced secondary and tertiary effects of this knockdown to LAMA4, a laminin encoding gene that contributes to the phenotype of triple-negative breast cancer. LAMA4-regulating miRNA miR-4274 and its host gene SORCS2 were highlighted as intermediate regulators of the expression levels of LAMA4, which correlated in a basal-like breast carcinoma sample subset of TCGA to the levels of SORCS2 negatively. Overall, our study points that the secondary and tertiary layers of regulatory interactions are certainly underappreciated. As these types of molecular event may significantly contribute to the formation of the cell phenotypes after RNA interference based knockdowns, further studies of multilayered molecular networks affected by RNAi are warranted.

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Метаболическое перепрограммирование трофобласта при моделировании ответа на гипоксию

2018 · ARTICLE · ru

Гипоксия клеток трофобласта является важным регулирующим фактором в процессе нормального развития плаценты. Однако воздействие гипоксии на плаценту при ряде патологических состояний, таких как преэклампсия, приводит к нарушению функций клеток. Производное оксихинолина способно ингибировать HIF-пролилгидроксилазы, стабилизируя таким образом транскрипционный комплекс HIF-1 и моделируя ответ клетки на гипоксию. Клетки хориокарциномы человека BeWo b30 используют для моделирования трофобласта, который является основой плацентарного барьера. При воздействии оксихинолина было выявлено не только повышение экспрессии целого ряда генов “ядра ответа” на гипоксию, но и повышение экспрессии генов NOS3, PDK1, BNIP3 и снижение экспрессии гена PPARGC1B. Это указывает на активацию механизмов метаболического перепрограммирования клеток, направленного на снижение потребления кислорода за счет уменьшения числа митохондрий и перехода от аэробного метаболизма глюкозы к анаэробному. Обсуждается возможность практического применения полученных результатов.

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Cell-Free Circulating Nucleic Acids as Early Biomarkers for NAFLD and NAFLD-Associated Disorders

2018 · ARTICLE · en

Non-alcoholic fatty liver disease (NAFLD) is the worldwide most common cause of chronic liver pathology, which prevalence strongly correlates with the increasing incidence of diabetes, obesity and metabolic syndrome in the general population. Simple steatosis, the earliest NAFLD stage, usually remains asymptomatic, and appropriate changes in the lifestyle, as well as the diet, can reverse the affected liver into the healthy state. The potential of simple steatosis to progress into severe fibrotic stages and to facilitate carcinogenesis necessitates timely NAFLD detection and risk stratification in community-based healthcare settings. Since their initial discovery a decade ago, extracellular circulating miRNAs have been found in all human biological fluids including blood and shown to hold great promises as non-invasive biomarkers. Normally, intracellular miRNAs participate in the regulation of gene expression, but once released by dying/dead cells they remain highly stable in the extracellular environment for prolonged periods. Therefore, circulating miRNA profiles can reflect the ongoing pathogenic processes in body's tissues and organs, and enable highly sensitive non-invasive diagnosis of multiple disorders. A non-urgent character of the NAFLD-related decision-making justifies the use of chronic liver diseases as an excellent test case for examining the practical utility of circulating miRNAs as biomarkers for longitudinal monitoring of human health. In this review, we summarize the state-of-the-art in the field of early diagnosis of NAFLD using circulating blood miRNAs, and stress the necessity of additional experimental validation of their diagnostic potential. We further emphasize on the potential diagnostics promises of other cell-free RNA species found in human biological fluids.

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Adipose may actively delay progression of NAFLD by releasing tumor-suppressing, anti-fibrotic miR-122 into circulation

2018 · ARTICLE · en

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue-cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR-122 falls, while the secretion of miRNA-containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver-supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease-associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR-122 and, possibly, some other miRNAs may be efficient for preventing NAFLD-associated hepatocellular carcinoma. The best candidates for exosome-wrapped miRNA producer are adipose tissue-derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC-derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co-manufactured along with their cargo. Exosome-delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.

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Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord

2018 · ARTICLE · en

The endogenous opioid system (EOS) controls the processing of nociceptive stimuli and is a pharmacological target for opioids. Alterations in expression of the EOS genes under neuropathic pain condition may account for low efficacy of opioid drugs. We here examined whether EOS expression patterns are altered in the lumbar spinal cord of the rats with spinal nerve ligation (SNL) as a neuropathic pain model. Effects of the left- and right-side SNL on expression of EOS genes in the ipsi- and contralateral spinal domains were analysed. The SNL-induced changes were complex and different between the genes; between the dorsal and ventral spinal domains; and between the left and right sides of the spinal cord. Prodynorphin (Pdyn) expression was upregulated in the ipsilateral dorsal domains by each the left and right-side SNL, while changes in expression of μ-opioid receptor (Oprm1) and proenkephalin (Penk) genes were dependent on the SNL side. Changes in expression of the Pdyn and κ-opioid receptor (Oprk1) genes were coordinated between the ipsi- and contralateral sides. Withdrawal response thresholds, indicators of mechanical allodynia correlated negatively with Pdyn expression in the right ventral domain after right side SNL. These findings suggest multiple roles of the EOS gene products in spinal sensitization and changes in motor reflexes, which may differ between the left and right sides.

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Cumulative prognostic power of laminin genes in colorectal cancer

2018 · ARTICLE · en

Background: Laminins are a major family of extracellular matrix proteins and the main component of basement membranes. Laminins are involved in many if not all stages of cancer progression, and expression of laminin genes has prognostic value in various types of cancer, including colorectal. Only single laminin genes or components of a single laminin trimer with significant differential expression have been regarded as potential biomarkers to date. Results: Here we compared prognostic power of classifiers constructed from sets of laminin genes with that of any single laminin gene. The analysis showed that cumulative prognostic power of sets of laminin genes was higher and was achieved already with pairs and triples of the genes. Interestingly, components of the pairs and the triples did not belong to any known laminin trimer, but, taken together with the gene weights, suggested higher LAMA4/ LAMA5 expression ratio in patients with poor prognosis. Conclusions: Analysis of the laminin expression profile rather than expression of the single genes or components of laminin trimers is useful for colorectal cancer prognosis in patients. High LAMA4/LAMA5 ratio is associated with increased permeability of basement membranes suggesting that basement membranes produced by colorectal tumors might be an important hindrance to their own dissemination in patients.

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In vitro and in silico liver models: Current trends, challenges and opportunities

2018 · ARTICLE · en

Most common drug development failures originate from either bioavailability problems, or unexpected toxic effects. The culprit is often the liver, which is responsible for biotransformation of a majority of xenobiotics. Liver may be modeled using "liver on a chip" devices, which may include established cell lines, primary human cells, and stem cell-derived hepatocyte-like cells. The choice of biological material along with its processing and maintenance greatly influence both the device performance and the resultant toxicity predictions. Impediments to the development of "liver on a chip" technology include the problems with standardization of cells, limitations imposed by culturing and the necessity to develop more complicated fluidic contours. Fortunately, recent breakthroughs in the development of cell-based reporters, including ones with fluorescent label, permits monitoring of the behavior of the cells embed into the "liver on a chip" devices. Finally, a set of computational approaches has been developed to model both particular toxic response and the homeostasis of human liver as a whole; these approaches pave a way to enhance the in silico stage of assessment for a potential toxicity.

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Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies

2018 · ARTICLE · en

Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam's metabolic liver pathways and other pharmacokinetic features. To determine phenazepam's metabolic pathways, the study was divided into three stages: In silico modeling, in vitro experiment (cell culture study), and in vivo confirmation. In silico modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The in vitro study was performed using a hepatocytes' cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam's metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients. According to in silico and in vitro analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the in vivo study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94-4.65] to 2.79 [95% CI: 2.02-3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam. Experimental in silico and in vivo studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.

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Курсы (6)