Трансгенные модельные объекты нового поколения и их использование в персонализированной медицине

В обзоре рассмотрены основные направления работы с модельными организмами (Danio rerio, Mus musculus) в области современной персонализированной медицины, представлены основные подходы к трансгенезу, позволяющие более точно моделировать конкретные патологии человека. Описаны существующие модельные системы для изучения атеросклероза, дислипидемических растройств, нейродегенеративных заболеваний. Упомянуты трехмерные клеточные технологии, применимые в рамках персонализированного подхода к пациенту.

1. Hall B, Limaye A, Kulkarni AB. Overview: generation of gene knockout mice. Curr Protoc Cell Biol. 2009;Chapter 19:Unit-19.12.17. DOI: 10.1002/0471143030.cb1912s441.

2. Ayadi A, Birling M-C, Bottomley J, et al. Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project. Mamm Genome. 2012;23(9-10):600–610. DOI: 10.1007/s00335-012-9418-y.

3. Misra RP, Duncan SA. Gene targeting in the mouse: advances in introduction of transgenes into the genome by homologous recombination. Endocrine. 2002;3(19):229–238.

4. Picciotto MR, Wickman K. Using knockout and transgenic mice to study neurophysiology and behavior. Physiological Reviews. 1998;4(78):1131–1163.

5. Pease S, Saunders TL. Advanced Protocols for Animal Transgenesis: An ISTT Manual. Berlin Heidelberg: Springer-Verlag, 2011.

6. Brenner M. Structure and transcriptional regulation of the GFAP gene. Brain Pathology. 1994;3(4):245–257.

7. Martin DI, Whitelaw E. The vagaries of variegating transgenes. BioEssays. 1996;18(11):919–923. DOI: 10.1002/bies.950181111.

8. Gilbert WV. Alternative ways to think about cellular internal ribosome entry. J Biol Chem. 2010;285(38):29033–29038.

9. Heintz N. BAC to the future: the use of bac transgenic mice for neuroscience research. Nature Reviews. Neuroscience. 2001;2(12):861–870.

10. Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992;89(12):5547–5551.

11. Kistner A, Gossen M, Zimmermann F. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A. 1996;93(20):10933–10938.

12. Schönig K, Bujard H, Gossen M. The power of reversibility regulating gene activities via tetracyclinecontrolled transcription. Methods in Enzymology. 2010;477:429–453.

13. Kim H, Kim M, Im SK, et al. Mouse Cre-LoxP system: general principles to determine tissue-specific roles of target genes. Lab Anim Res. 2018;34(4):147-159. DOI: 10.5625/lar.2018.34.4.147

14. Hirrlinger J, Requardt RP, Winkler U, et al. Split-CreERT2: Temporal Control of DNA Recombination Mediated by Split-Cre Protein Fragment Complementation. PLoS One. 2009;4(12): e8354. DOI: 10.1371/JOURNAL.PONE.0008354.

15. Sando R 3rd, Baumgaertel K, Pieraut S, et al. Inducible control of gene expression with destabilized Cre. Nat Methods. 2013;10(11):1085-1088. DOI: 10.1038/nmeth.2640.

16. Pan YA, Freundlich T, Weissman TA, et al. Zebrabow: multispectral cell labeling for cell tracing and lineage analysis in zebrafish. Development. 2013;140(13):2835-2846. DOI: 10.1242/dev.094631

17. Weissman TA, Pan YA. Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis. Genetics. 2015;199(2):293-

18. DOI: 10.1534/genetics.114.172510

19. Kastriti ME, Kameneva P, Kamenev D, et al. Schwann Cell Precursors Generate the Majority of Chromaffin Cells in Zuckerkandl Organ and Some Sympathetic Neurons in Paraganglia. Front Mol Neurosci. 2019;12:6. DOI: 10.3389/fnmol.2019.00006.

20. Bayguinov PO, Ma Y, Gao Y, et al. Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor. J Neurosci. 2017;37(38):9305-9319. DOI: 10.1523/JNEUROSCI.1363-17.2017.

21. DeNardo L, Luo L. Genetic strategies to access activated neurons. Curr Opin Neurobiol. 2017;45:121-129. DOI: 10.1016/j.conb.2017.05.014.

22. Castello-Waldow TP, Weston G, Ulivi Af, et al. Hippocampal neurons with stable excitatory connectivity become part of neuronal representations. PLoS Biol. 2020;18(11):e3000928. DOI: 10.1371/journal.pbio.3000928.

23. Phan QV, Contzen J, Seemann P, et al. Sitespecific chromosomal gene insertion: Flp recombinase versus Cas9 nuclease. Sci Rep. 2017;7(1):17771. DOI: 10.1038/s41598-017-17651-0.

24. Karimova M, Baker O, Camgoz A, et al. A single reporter mouse line for Vika, Flp, Dre, and Crerecombination. Sci Rep. 2018;8(1):14453. DOI: 10.1038/s41598-018-32802-7.

25. Gut P, Reischauer S, Stainier DYR, et al. Little fish, big data: zebrafish as a model for cardiovascular and metabolic disease. Physiol Rev. 2017;97:889–938. DOI: 10.1152/physrev.00038.2016

26. Sehnert AJ, Huq A, Weinstein BM, et al. Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. Nature Genetics. 2002;31(1):106-110.

27. Thisse C, Zon LI. Organogenesis--heart and blood formation from the zebrafish point of view. Science. 2002;295(5554):457-462.

28. Jurczyk A, Roy N, Bajwa R, et al. Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish. Gen Comp Endocrinol. 2011;170(2):334-345.

29. Ober EA, Field HA, Stainier DY. From endoderm formation to liver and pancreas development in zebrafish. Mechanisms of Development. 2003;120(1):5-18.

30. Schlegel A, Stainier DY. Lessons from “Lower” Organisms: What Worms, Flies, and Zebrafish Can Teach Us about Human Energy Metabolism. PLoS Genetics. 2007;3(11):e199.

31. Cao J, Navis A, Cox BD, et al. Single epicardial cell transcriptome sequencing identifies Caveolin-1 as an essential factor in zebrafish heart regeneration. Development. 2016;143(2):232-243.

32. / unker JP, Noël ES, Guryev V, et al. Genomewide RNA Tomography in the Zebrafish Embryo. Cell. 2014;159:662-675.

33. Lee R, Thiery JP, Carney TJ. Dermal fin rays and scales derive from mesoderm, not neural crest. Current biology. 2013;23(9):R336-337.

34. Nolte H, Hölper S, Housley MP, et al. Dynamics of zebrafish fin regeneration using a pulsed SILAC approach. Proteomics. 2015;15(4):739-751.

35. Fraher D, Hodge JM, Collier FM, et al. Citalopram and sertraline exposure compromises embryonic bone development. Molecular Psychiatry. 2016;21(5):656-664.

36. Gupta V, Poss KD. Clonally dominant cardiomyocytes direct heart morphogenesis. Nature. 2012;484(7395):479-484.

37. Song Z, Zhang X, Jia S, et al. Zebrafish as a Model for Human Ciliopathies. Journal of genetics and genomics = Yi chuan xue bao. 2016;43:107-20.

38. Howe DG, Bradford YM, Conlin T, et al. ZFIN, the Zebrafish Model Organism Database: increased support for mutants and transgenics. Nucleic acids research. 2013;41(D1):D854-860.

39. Dahlem TJ, Hoshijima K, Jurynec MJ, et al. Simple Methods for Generating and Detecting Locus- Specific Mutations Induced with TALENs in the Zebrafish Genome. PLoS Genet 2012;8(8):e1002861. DOI: 10.1371/journal.pgen.1002861.

40. Cornet C, Di Donato V, Terriente J. Combining Zebrafish and CRISPR/Cas9: Toward a More Efficient Drug Discovery Pipeline. Front Pharmacol. 2018;9:703. DOI: 10.3389/fphar.2018.00703.

41. Baxendale S, van Eeden F, Wilkinson R. The Power of Zebrafish in Personalised Medicine. Adv Exp Med Biol. 2017;1007:179-197. DOI: 10.1007/978-3-319-60733-7_10.

42. Fish RJ, Di Sanza C, Neerman-Arbez M. Targeted mutation of zebrafish fga models human congenital afibrinogenemia. Blood. 2014;123:2278-2281.

43. Wilkinson RN, Jopling C, van Eeden FJ. Zebrafish as a model of cardiac disease. Progress in molecular biology and translational science. 2014;124:65-91.

44. Schmid B, Haass C. Genomic editing opens new avenues for zebrafish as a model for neurodegeneration. Journal of neurochemistry. 2013;127(4):461-470.

45. Runtuwene V, van Eekelen M, Overvoorde J, et al. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. Disease models & mechanisms. 2011;4(3):393-399.

46. Seda M, Peskett E, Demetriou C, et al. Analysis of transgenic zebrafish expressing the Lenz-Majewski syndrome gene PTDSS1 in skeletal cell lineages. F1000Research. 2019;8:273.

47. O’Donnell KC, Lulla A, Stahl MC, et al. Axon degeneration and PGC-1alpha-mediated protection in a zebrafish model of alpha-synuclein toxicity. Disease models & mechanisms. 2014;7:571-582.

48. Ohki Y, Wenninger-Weinzierl A, Hruscha A, et al. Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration. Molecular Neurodegeneration. 2017;12:6.

49. Issa FA, Mazzochi C, Mock AF, et al. Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2011;31(18):6831-6841.

50. Getz GS, Reardon CA. Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(5):1104–1115. DOI: 10.1161/ATVBAHA.111.237693.NIH

51. Badimon L, Vilahur G. Thrombosis formation on atherosclerotic lesions and plaque rupture. J Intern Med. 2014;276(6):618-32. DOI: 10.1111/joim.12296.

52. Vedder VL, Aherrahrou Z, Erdmann J. Dare to Compare. Development of Atherosclerotic Lesions in Human, Mouse, and Zebrafish. Front Cardiovasc Med. 2020;7:109. DOI: 10.3389/fcvm.2020.00109.

53. Chao L, Gates KP, Fang L, et al. Apoc2 lossof- function zebrafish mutant as a genetic model of hyperlipidemia. Dis Models Mech. 2015;8(8):989-998. DOI: 10.1242/dmm.019836.

54. Chao Liu, Young Sook Kim, Jungsu Kim, et al. Modeling hypercholesterolemia and vascular lipid accumulation in LDL receptor mutant zebrafish. J Lipid Res. 2018;59(2):391-399. DOI: 10.1194/jlr.D081521.

55. Jun Ka, Suk-Won Jin. J, Zebrafish as an Emerging Model for Dyslipidemia and Associated Diseases. J Lipid Atheroscler. 2021;10(1):42-56. DOI: 10.12997/jla.2021.10.1.42.

56. Jun Ka, Boryeong Pak, Orjin Han, et al. Comparison of transcriptomic changes between zebrafish and mice upon high fat diet reveals evolutionary convergence in lipid metabolism. Biochem Biophys Res Commun. 2020;530(4):638-643. DOI: 10.1016/j.bbrc.2020.07.042.

57. Schlegel A. Zebrafish models for dyslipidemia and atherosclerosis research. Front Endocrinol (Lausanne). 2016;7:159. DOI: 10.3389/fendo.2016.00159.

58. Christiaens V, Lijnen HR. Angiogenesis and development of adipose tissue. Mol Cell Endocrinol. 2010;318:2–9.

59. Ridker PM, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131.

60. Baragetti A, Catapano AL, Magni P. Multifactorial Activation of NLRP3 Inflammasome: Relevance for a Precision Approach to Atherosclerotic Cardiovascular Risk and Disease. Int J Mol Sci. 2020;21(12):4459. DOI: 10.3390/ijms21124459.

61. Li JY, Wang YY, Shao T, et al. The zebrafish NLRP3 inflammasome has functional roles in ASCdependent interleukin-1β maturation and gasdermin E-mediated pyroptosis. J Biol Chem. 2020;295(4):1120-1141. DOI: 10.1074/jbc.RA119.011751.

62. Milichko V, Dyachuk V. Novel glial cell functions: extensive potency, stem cell-like properties, and participation in regeneration and transdifferentiation. Frontiers in Cell and Developmental Biology. 2020. DOI: 10.3389/fcell.2020.00809.

63. Dyachuk V, Furlan A, Shahidi MK, et al. Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. Science. 2014;345(6192):82-87.

64. Sauer B. Functional expression of the crelox site-specific recombination system in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1987;7:2087–2096.

65. Golic KG, Lindquist S. The FLP recombinase of yeast catalyzes site-specific recombination in the drosophila genome. Cell. 1989;59:499–509.

66. Dhaliwal J, Lagace DC. Visualization and genetic manipulation of adult neurogenesis using transgenic mice. Eur J Neurosci. 2011;33:1025–1036.

67. Lacar B, Young SZ, Platel J-C, et al. Imaging and recording subventricular zone progenitor cells in live tissue of postnatal mice. Front Neurosci 2010;4:1–16.

68. Livet J, Weissman TA, Kang H, et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature. 2007;450:56–62.

69. Weber K, Thomaschewski M, Warlich M, et al (2011) RGB marking facilitates multicolor clonal cell tracking. Nat Med. 2011;17(4):504-509. DOI: 10.1038/nm.2338.

70. García-Marqués J, López-Mascaraque L. Clonal identity determines astrocyte cortical heterogeneity. Cereb Cortex. 2013;23:1463–1472. DOI: 10.1093/CERCOR/BHS134.

71. Kumamoto T, Maurinot F, Barry-Martinet R, et al. Direct readout of neural stem cell transgenesis with an integration-coupled gene expression switch. Neuron. 2020;107(4):617-630.e6. DOI: 10.1016/j.neuron.2020.05.038.

72. Loulier K, Barry R, Mahou P, et al. Multiplex cell and lineage tracking with combinatorial labels. Neuron. 2014;81:505–520. DOI: 10.1016/J.NEURON.2013.12.016.

73. Abdeladim L, Matho KS, Clavreul S, et al. Multicolor multiscale brain imaging with chromatic multiphoton serial microscopy. Nat Commun. 2019;10:1–14. DOI: 10.1038/S41467-019-09552-9.

74. Hirokazu Kaji, Takeshi Yokoi, Takeaki Kawashima, et al. Controlled cocultures of HeLa cells and human umbilical vein endothelial cells on detachable substrates. Lab Chip. 2009;9(3):427-432. DOI: 10.1039/b812510d.

75. Kim H, Yi N, Do B, et al. Adipose-derived stem cell coculturing stimulates integrin-mediated extracellular matrix adhesion of melanocytes by upregulating growth factors. Biomolecules & Therapeutics. 2019;27:185-192. doi: 10.4062/biomolther.2018.203.

76. Zeng Q, Chen W. The functional behavior of a macrophage/fibroblast co-culture model derived from normal and diabetic mice with a marine gelatin-oxidized alginate hydrogel. Biomaterials. 2010;31(22):5772-5781. DOI: 10.1016/j.biomaterials.2010.04.022.

77. Trujillo CA, Gao R, Negraes PD, et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell. 2019;25(4):558-569.e7. DOI: 10.1016/j.stem.2019.08.002.

78. Signati L, Allevi R, Piccotti F, et al. Ultrastructural analysis of breast cancer patient-derived organoids. Cancer Cell Int. 2021;21(1):423. DOI: 10.1186/s12935-021-02135-z.

79. Xu H, Lyu X, Yi M, et al. Organoid technology and applications in cancer research. J Hematol Oncol. 2018;11(1):116. DOI: 10.1186/s13045-018-0662-9.

80. Gopal S, Rodrigues AL, Dordick JS. Exploiting CRISPR Cas9 in Three-Dimensional Stem Cell Cultures to Model Disease. Front Bioen Biotechnol. 2020;8:692. DOI: 10.3389/fbioe.2020.00692.

81. Teriyapirom I, Batista-Rocha AS, Koo BK. Genetic engineering in organoids. J Mol Med. 2021;99:555–568. DOI: 10.1007/s00109-020-02029-z.

82. Lupo F, Piro G, Torroni L, et al. Organoid- Transplant Model Systems to Study the Effects of Obesity on the Pancreatic Carcinogenesis in vivo. Front Cell Dev Biol. 2020;8:308. DOI: 10.3389/fcell.2020.00308.