Гаража Андрей Владимирович

Образование

Период обученияСтрана, городУчебное заведениеДополнительная информация
2007–2011 Россия, Москва Московский Физико-Технический Институт (МФТИ), факультет молекулярной и биологической физики степень бакалавра по специальности "Прикладная физика и математика"
2011–2013 Россия, Москва Московский Физико-Технический Институт (МФТИ), факультет молекулярной и биологической физики степень магистра по специальности "Прикладная физика и математика"

Научные интересы

Молекулярная биология, генетика, биоинформатика, психогенетика. Изучение транскрипционной активности мобильных элементов генома.

Избранные публикации

  1. Aliper A., Belikov A.V., Garazha A., Jellen L., Artemov A., Suntsova M., Ivanova A., Venkova L., Borisov N., Buzdin A., Mamoshina P., Putin E., Swick A.G., Moskalev A., Zhavoronkov A. (2016). In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging (Albany NY) 8 (9), 2127–2152 [+]

    Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.

    ID:1575
  2. Suntsova M., Garazha A., Ivanova A., Kaminsky D., Zhavoronkov A., Buzdin A. (2015). Molecular functions of human endogenous retroviruses in health and disease. Cell. Mol. Life Sci. 72 (19), 3653–75 [+]

    Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

    ID:1413
  3. Moskalev A., Chernyagina E., deMagalhães J.P., Barardo D., Thoppil H., Shaposhnikov M., Budovsky A., Fraifeld V.E., Garazha A., Tsvetkov V., Bronovitsky E., Bogomolov V., Scerbacov A., Kuryan O., Gurinovich R., Jellen L.C., Kennedy B., Mamoshina P., Dobrovolskaya E., Aliper A., Kaminsky D., Zhavoronkov A. (2015). Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY) 7 (9), 616–28 [+]

    As the level of interest in aging research increases, there is a growing number of geroprotectors, or therapeutic interventions that aim to extend the healthy lifespan and repair or reduce aging-related damage in model organisms and, eventually, in humans. There is a clear need for a manually-curated database of geroprotectors to compile and index their effects on aging and age-related diseases and link these effects to relevant studies and multiple biochemical and drug databases. Here, we introduce the first such resource, Geroprotectors (http://geroprotectors.org). Geroprotectors is a public, rapidly explorable database that catalogs over 250 experiments involving over 200 known or candidate geroprotectors that extend lifespan in model organisms. Each compound has a comprehensive profile complete with biochemistry, mechanisms, and lifespan effects in various model organisms, along with information ranging from chemical structure, side effects, and toxicity to FDA drug status. These are presented in a visually intuitive, efficient framework fit for casual browsing or in-depth research alike. Data are linked to the source studies or databases, providing quick and convenient access to original data. The Geroprotectors database facilitates cross-study, cross-organism, and cross-discipline analysis and saves countless hours of inefficient literature and web searching. Geroprotectors is a one-stop, knowledge-sharing, time-saving resource for researchers seeking healthy aging solutions.

    ID:1414
  4. Garazha A., Ivanova A., Suntsova M., Malakhova G., Roumiantsev S., Zhavoronkov A., Buzdin A. (2015). New bioinformatic tool for quick identification of functionally relevant endogenous retroviral inserts in human genome. Cell Cycle 14 (9), 1476–84 [+]

    Endogenous retroviruses (ERVs) and LTR retrotransposons (LRs) occupy ∼8% of human genome. Deep sequencing technologies provide clues to understanding of functional relevance of individual ERVs/LRs by enabling direct identification of transcription factor binding sites (TFBS) and other landmarks of functional genomic elements. Here, we performed the genome-wide identification of human ERVs/LRs containing TFBS according to the ENCODE project. We created the first interactive ERV/LRs database that groups the individual inserts according to their familial nomenclature, number of mapped TFBS and divergence from their consensus sequence. Information on any particular element can be easily extracted by the user. We also created a genome browser tool, which enables quick mapping of any ERV/LR insert according to genomic coordinates, known human genes and TFBS. These tools can be used to easily explore functionally relevant individual ERV/LRs, and for studying their impact on the regulation of human genes. Overall, we identified ∼110,000 ERV/LR genomic elements having TFBS. We propose a hypothesis of "domestication" of ERV/LR TFBS by the genome milieu including subsequent stages of initial epigenetic repression, partial functional release, and further mutation-driven reshaping of TFBS in tight coevolution with the enclosing genomic loci.

    ID:1289
  5. Spirin P.V., Lebedev T.D., Orlova N.N., Gornostaeva A.S., Prokofjeva M.M., Nikitenko N.A., Dmitriev S.E., Buzdin A.A., Borisov N.M., Aliper A.M., Garazha A.V., Rubtsov P.M., Stocking C., Prassolov V.S. (2014). Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling. Leukemia 28 (11), 2222–8 [+]

    The t(8;21)(q22;q22) rearrangement represents the most common chromosomal translocation in acute myeloid leukemia (AML). It results in a transcript encoding for the fusion protein AML1-ETO (AE) with transcription factor activity. AE is considered to be an attractive target for treating t(8;21) leukemia. However, AE expression alone is insufficient to cause transformation, and thus the potential of such therapy remains unclear. Several genes are deregulated in AML cells, including KIT that encodes a tyrosine kinase receptor. Here, we show that AML cells transduced with short hairpin RNA vector targeting AE mRNAs have a dramatic decrease in growth rate that is caused by induction of apoptosis and deregulation of the cell cycle. A reduction in KIT mRNA levels was also observed in AE-silenced cells, but silencing KIT expression reduced cell growth but did not induce apoptosis. Transcription profiling of cells that escape cell death revealed activation of a number of signaling pathways involved in cell survival and proliferation. In particular, we find that the extracellular signal-regulated kinase 2 (ERK2; also known as mitogen-activated protein kinase 1 (MAPK1)) protein could mediate activation of 23 out of 29 (79%) of these upregulated pathways and thus may be regarded as the key player in establishing the t(8;21)-positive leukemic cells resistant to AE suppression.

    ID:1290
  6. Zhavoronkov A., Buzdin A.A., Garazha A.V., Borisov N.M., Moskalev A.A. (2014). Signaling pathway cloud regulation for in silico screening and ranking of the potential geroprotective drugs. Front Genet 5, 49 [+]

    The major challenges of aging research include absence of the comprehensive set of aging biomarkers, the time it takes to evaluate the effects of various interventions on longevity in humans and the difficulty extrapolating the results from model organisms to humans. To address these challenges we propose the in silico method for screening and ranking the possible geroprotectors followed by the high-throughput in vivo and in vitro validation. The proposed method evaluates the changes in the collection of activated or suppressed signaling pathways involved in aging and longevity, termed signaling pathway cloud, constructed using the gene expression data and epigenetic profiles of young and old patients' tissues. The possible interventions are selected and rated according to their ability to regulate age-related changes and minimize differences in the signaling pathway cloud. While many algorithmic solutions to simulating the induction of the old into young metabolic profiles in silico are possible, this flexible and scalable approach may potentially be used to predict the efficacy of the many drugs that may extend human longevity before conducting pre-clinical work and expensive clinical trials.

    ID:1291
  7. Suntsova M., Gogvadze E.V., Salozhin S., Gaifullin N., Eroshkin F., Dmitriev S.E., Martynova N., Kulikov K., Malakhova G., Tukhbatova G., Bolshakov A.P., Ghilarov D., Garazha A., Aliper A., Cantor C.R., Solokhin Y., Roumiantsev S., Balaban P., Zhavoronkov A., Buzdin A. (2013). Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH. Proc. Natl. Acad. Sci. U.S.A. , [+]

    Using a systematic, whole-genome analysis of enhancer activity of human-specific endogenous retroviral inserts (hsERVs), we identified an element, hsERVPRODH, that acts as a tissue-specific enhancer for the PRODH gene, which is required for proper CNS functioning. PRODH is one of the candidate genes for susceptibility to schizophrenia and other neurological disorders. It codes for a proline dehydrogenase enzyme, which catalyses the first step of proline catabolism and most likely is involved in neuromediator synthesis in the CNS. We investigated the mechanisms that regulate hsERVPRODH enhancer activity. We showed that the hsERVPRODH enhancer and the internal CpG island of PRODH synergistically activate its promoter. The enhancer activity of hsERVPRODH is regulated by methylation, and in an undermethylated state it can up-regulate PRODH expression in the hippocampus. The mechanism of hsERVPRODH enhancer activity involves the binding of the transcription factor SOX2, whch is preferentially expressed in hippocampus. We propose that the interaction of hsERVPRODH and PRODH may have contributed to human CNS evolution.

    ID:920
  8. Zabolotneva A.A., Zhavoronkov A.A., Shegay P.V., Gaifullin N.M., Alekseev B.Y., Roumiantsev S.A., Garazha A.V., Kovalchuk O., Aravin A., Buzdin A.A. (2013). A systematic experimental evaluation of microRNA markers of human bladder cancer. Front Genet 4, 247 [+]

    MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. They are aberrantly expressed in many human cancers and are potential therapeutic targets and molecular biomarkers.

    ID:1292
  9. Baskaev K., Garazha A., Gaifullin N., Suntsova M.V., Zabolotneva A.A., Buzdin A.A. (2012). nMETR: Technique for facile recovery of hypomethylation genomic tags. Gene , [+]

    Genome-wide methylation studies frequently lack adequate controls to estimate proportions of background reads in the resulting datasets. To generate appropriate control pools, we developed technique termed nMETR (non-methylated tag recovery) based on digestion of genomic DNA with methylation-sensitive restriction enzyme, ligation of adapter oligonucleotide and PCR amplification of non-methylated sites associated with genomic repetitive elements. The protocol takes only two working days to generate amplicons for deep sequencing. We applied nMETR for human DNA using BspFNI enzyme and retrotransposon Alu-specific primers. 454-sequencing enabled identification of 1113 nMETR tag sites, of them ~65% were parts of CpG islands. Representation of reads inversely correlated with methylation levels, thus confirming nMETR fidelity. We created software that eliminates background reads and enables to map and annotate individual tags on human genome. nMETR tags may serve as the controls for large-scale epigenetic studies and for identifying unmethylated transposable elements located close to genomic CpG islands.

    ID:667
  10. Zabolotneva A.A., Zhavoronkov A., Garazha A.V., Roumiantsev S.A., Buzdin A.A. (2012). Characteristic patterns of microRNA expression in human bladder cancer. Front Genet 3, 310 [+]

    MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Their altered expression and functional activity have been observed in many human cancers. miRNAs represent promising diagnostic and prognostic molecular biomarkers, and also serve as novel therapeutic targets. We performed a systematic analysis of scientific reports that link differences in miRNA expression with the pathogenesis of bladder cancer (BC). This literature review is the first comprehensive database of miRNA molecules with biased expression profiles in BC. Among the 95 differentially expressed miRNAs that we identified from the literature, we classify 48 as up-regulated in BC, 35 as down-regulated, and 12 as contradictory (contradictory data were reported in one or more studies on the gene). In addition, we discuss the possible roles of differentially expressed miRNAs in the regulation of intracellular signaling pathways in BC.

    ID:838