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Никулин Сергей Вячеславович

Аспирантская школа по биологии

Профиль на hse.ru ↗ тел.: 15093
Публикаций
37
Языков
1
Наград
6
Конференций
2
Профиль Публикации (37) Курсы (9)

Профессиональные интересы

модель кишечника человека in vitroонкологияперсонифицированная медицинабиоинформатикамолекулярная биологиябиология ракаклеточная биология3-х мерные клеточные моделибиохимия

Должности

  • Академический директор — Аспирантская школа по биологии
  • Доцент — Факультет биологии и биотехнологии, Базовая кафедра Института биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН
  • Старший научный сотрудник — Факультет биологии и биотехнологии, Лаборатория исследований молекулярных механизмов долголетия
  • Ведущий научный сотрудник — Факультет биологии и биотехнологии, Международная лаборатория микрофизиологических систем

Био

  • · Начал работать в НИУ ВШЭ в 2020 году.

Образование

  • 2020 · Кандидат биологических наук: Московский физико-технический институт (национальный исследовательский университет)
  • 2019 · Аспирантура: Московский физико-математический институт (государственный университет), специальность «Биологические науки», квалификация «Исследователь. Преподаватель-исследователь»
  • 2015 · Магистратура: Московский физико-технический институт (национальный исследовательский университет), специальность «Прикладная математика и физика», квалификация «Магистр прикладной математики и информатики»
  • 2013 · Бакалавриат: Московский физико-технический институт (национальный исследовательский университет), специальность «Прикладная математика и физика», квалификация «Бакалавр»

Опыт работы

  • · 2020: НИУ ВШЭ с года

Награды и поощрения

  • · Благодарность Министерства науки и высшего образования Российской Федерации (декабрь 2024)
  • · Надбавка за публикации, вносящие особый вклад в международную научную репутацию НИУ ВШЭ (2024–2027)
  • · Надбавка за публикацию в журнале из Списка А (и приравненном к нему научном издании) (2023–2024)
  • · Надбавка за публикацию в международном рецензируемом научном издании (2022–2023, 2021–2022, 2020–2021)
  • · Лучший преподаватель — 2023–2025
  • · Победитель Конкурса лучших русскоязычных научных и научно-популярных работ работников НИУ ВШЭ – 2023

Гранты и проекты

  • — · на соискание учёной степени кандидата наук

Конференции (2)

Показать все
  • · 2019: International Federation of Placenta Associations 2019 (IFPA2019); 8th Latin American Symposium on Maternal-Fetal Interaction and Placenta (VIII SLIMP), Buenos Aires, Argentina (Buenos Aires). Доклад: Application of impedance spectroscopy for analysis of BeWo clone b30 human choriocarcinoma cell line
  • · 2019: 22st European Congress on Alternatives to Animal Testing, 19th Annual Congress of EUSAAT, Linz, Austria (Linz). Доклад: Placenta-on-a-chip model for assessing the transport and toxicity of xenobiotics in vitro

Идентификаторы исследователя

Публикации (37)

Bach1 derepression is neuroprotective in a mouse model of Parkinson’s disease

2021 · ARTICLE · en

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor–induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD .

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ИССЛЕДОВАНИЕ ТОКСИЧНОСТИ КАЛИКС[4]- И [6]-АРЕНОВ И ИХ СУЛЬФАТИРОВАННЫХ ПРОИЗВОДНЫХ В ДВУМЕРНОЙ И ТРЕХМЕРНОЙ КУЛЬТУРЕ КЛЕТОЧНОЙ ЛИНИИ КОЛОРЕКТАЛЬНОЙ АДЕНОКАРЦИНОМЫ

2021 · ARTICLE · ru

Проведено сравнительное исследование токсичности двух незамещенных каликсаренов, состоящих из 4 и 6 фенольных фрагментов, а также их п-сульфатированных производных на клеточной линии HT-29 колоректальной аденокарциномы, культивируемой в двумерном (2D) и трехмерном (3D) форматах. Показано, что незамещенные каликсарены снижают жизнеспособность опухолевых клеток, причем каликс[4]арен проявлял цитостатический эффект, а каликс[6]арен - цитотоксический. Сульфопроизводные каликсаренов не оказывали выраженного токсического действия на клетки HT-29, однако, благодаря высокой гидрофильности и способности к образованию аддуктов с различными терапевтическими молекулами, могут быть использованы для повышения эффективности доставки противоопухолевых препаратов.

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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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Гипоксия усиливает трансцитоз в энтероцитах кишечника

2020 · ARTICLE · ru

Важнейшее условие нормального функционирования кишечника — сохранение барьерных функций монослоя эпительных клеток, выстилающих его поверхность. Воспалительные состояния кишечника, как правило, ассоциированы с дополнительной тканевой гипоксией, что приводит к нарушению целостности эпителия. Однако опасность инфекционных заболеваний может сохраняться и при отсутствии очевидных нарушений монослоя клеток. Возможная причина этого — изменение внутриклеточного транспорта везикул, содержащих бактерии. Целью работы было на модели энтероцитов кишечника человека исследовать влияние гипоксии на процесс трансцитоза. Показано, что гипоксия усиливает в 1,8 раза трансцитоз модельного белка, растительного лектина рицина. Сравнительное исследование транскриптомов и протеомов выявило достоверное изменение экспрессии генов, вовлеченных во внутриклеточный везикулярный транспорт, в том числе падение экспрессии регулятора метаболизма липидов apoB, как на уровне белка (в 6,5 раза), так и на уровне мРНК (в 2,1 раза). Необходимы работы по изучению возможного механизма регуляции экспрессии генов в энтероцитах кишечника в условиях гипоксии.

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Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model

2020 · ARTICLE · en

A novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and HIF2 target genes and shows no toxicity up to 20 μM, which is more than an order of magnitude higher than its biologically active concentration. Cell viability, functional activity, and network connectivity between the elements of neuronal networks have been studied using a pairwise correlation analysis of the intracellular calcium fluctuations in the individual cells. An immediate treatment with 1 μM and 15 μM neuradapt right at the onset of hypoxia not only protects from the death, but also maintains the spontaneous calcium activity in nervous cells at the level of the intact cultures. A similar neuroprotective effect in the post-treatment scenario is observed for 15 μM, but not for 1 μM neuradapt. Network connectivity is better preserved with immediate treatment using 1 μM neuradapt than with 15 μM, which is still beneficial. Post-treatment with neuradapt did not restore the network connectivity despite the observation that neuradapt significantly increased cell viability at 1 μM and functional activity at 15 μM. The preservation of cell viability and functional activity makes neuradapt promising for further studies in a post-treatment scenario, since it can be combined with other drugs and treatments restoring the network connectivity of functionally competent cells.

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Breast cancer organoid model allowed to reveal potentially beneficial combinations of 3,3′-diindolylmethane and chemotherapy drugs

2020 · ARTICLE · en

Epigenetic alterations represent promising therapeutic targets in cancer treatment. Recently it was revealed that small molecules have the potential to act as microRNA silencers. Capacity to bind the discrete stem-looped structure of pre-miR-21 and prevent its maturation opens opportunities to utilize such compounds for the prevention of initiation, progression, and chemoresistance of cancer. Molecular simulations performed earlier identified 3,3′-diindolylmethane (DIM) as a potent microRNA-21 antagonist. However, data on DIM and microRNA-21 interplay is controversial, which may be caused by the limitations of the cell lines. In this study, we established a tumor organoid culture from metastatic breast cancer and tested the efficiency of DIM in combination with common chemotherapeutic drugs used in clinic. Organoids shared morphologic features with the primary tumor, captured tumor heterogeneity, and possessed unique genetic characteristics. Here, we report that DIM suppresses mir-21-5p expression and enhances susceptibility of patient-derived breast cancer organoid to cyclophosphamide and methotrexate treatment. Our data support the hypothesis that small molecules can be utilized as microRNA silencers to overcome cancer-related drug resistance and other pathologies.

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Towards embedding Caco-2 model of gut interface in a microfluidic device to enable multi-organ models for systems biology

2019 · ARTICLE · en

A cancer cell line originating from human epithelial colorectal adenocarcinoma (Caco-2 cells) serves as a high capacity model for a preclinical screening of drugs. Recent need for incorporating barrier tissue into multi-organ chips calls for inclusion of Caco-2 cells into microperfused environment. This article describes a series of systems biology insights obtained from comparing Caco-2 models cells grown as conventional 2D layer and in a microfluidic chip. When basic electrical parameters of Caco-2 monolayers were evaluated using impedance spectrometry and MTT assays, no differences were noted. On the other hand, the microarray profiling of mRNAs and miRNAs revealed that grows on a microfluidic chip leads to the change in the production of specific miRNA, which regulate a set of genes for cell adhesion molecules (CAMs), and provide for more complete differentiation of Caco-2 monolayer. Moreover, the sets of miRNAs secreted at the apical surface of Caco-2 monolayers grown in conventional 2D culture and in microfluidic device differ. When integrated into a multi-tissue platform, Caco-2 cells may aid in generating insights into complex pathophysiological processes, not possible to dissect in conventional cultures.

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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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"Branched Tail" Oxyquinoline Inhibitors of HIF Prolyl Hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip

2019 · ARTICLE · en

BACKGROUND "Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection. OBJECTIVE The aim of the study is to characterize the toxicity and metabolism of adaptaquin and its new improved analogs. METHOD Liver-on-a-chip technology with differentiated HepaRG cells followed by LC-MS detection of the studied compounds and metabolites of the P450 substrate-inhibitor panel for CYP2B6, CYP2C9, CYP2C19, and CYP3A4. RESULTS The optimized adaptaquin analogs show no toxicity up to a 100-fold increased range over EC50. The drugs are metabolized by CYP3A4 and CYP2B6 as shown with the use of the cytochrome P450 substrate-inhibitor panel designed and optimized for preclinical evaluation of drugs' in vitro biotransformation on a 3D human histotypical cell model using "liver-on-a-chip" technology. Activation of CYP2B6 with the drugs tested has been observed. A scheme for adaptaquin oxidative conversion is proposed. CONCLUSION The optimized adaptaquin analogs are suitable for further preclinical trials. Activation of CYP2B6 with adaptaquin and its variants points to a potential increase in Tylenol toxicity if administered together.

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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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Курсы (9)