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'''Chemical genetics''' is the investigation of the function of [[protein]]s and [[signal transduction]] pathways in cells by the [[high-throughput screening|screening]] of [[chemical library|chemical libraries]] of [[small molecule]]s.<ref name="isbn3-540-27865-6">{{cite book |veditors= Weinmann H, Jaroch S | title = Chemical genomics small molecule probes to study cellular function | publisher = Springer | location = Berlin | year = 2006 | isbn = 978-3-540-27865-8 | chapter = Chemogenomics in drug discovery | author = Kubinyi H }}</ref> Chemical genetics is analogous to classical [[genetic screen]] where random mutations are introduced in organisms, the [[phenotype]] of these mutants is observed, and finally the specific gene mutation ([[genotype]]) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds. [[Phenotypic screening]] of chemical libraries is used to identify drug targets ([[forward genetics]] or [[chemoproteomics]]) or to validate those targets in experimental models of disease ([[reverse genetics]]).<ref name="isbn3-527-30987-X">{{cite book |veditors= Folkers G, Kubinyi H, Müller G, Mannhold R | title = Chemogenomics in drug discovery: a medicinal chemistry perspective | publisher = Wiley-VCH | location = Weinheim | year = 2004 | pages = [https://archive.org/details/chemogenomicsind00kubi/page/69 69–96] | isbn = 978-3-527-30987-0 | chapter = The value of chemical genetics in drug discovery |vauthors=Russel K, Michne WF | chapter-url-access = registration | chapter-url = https://archive.org/details/chemogenomicsind00kubi/page/69 }}</ref> Allelic Scanning (forward genetics) is also used to map loci of interest by determining if the specific loci is responsible for the phenotypic appearance.<ref>{{cite journal | vauthors = Stockwell BR | title = Chemical genetics: ligand-based discovery of gene function | journal = Nature Reviews. Genetics | volume = 1 | issue = 2 | pages = 116–125 | date = November 2000 | pmid = 11253651 | pmc = 3171795 | doi = 10.1038/35038557 }}</ref> Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments.<ref>{{cite journal | vauthors = Carlson SM, White FM | title = Expanding applications of chemical genetics in signal transduction | journal = Cell Cycle | volume = 11 | issue = 10 | pages = 1903–1909 | date = May 2012 | pmid = 22544320 | pmc = 3359120 | doi = 10.4161/cc.19956 }}</ref> Chemical genetics can serve as a unifying study between chemistry and biology.<ref>{{cite journal | vauthors = O'Connor CJ, Laraia L, Spring DR | title = Chemical genetics | journal = Chemical Society Reviews | volume = 40 | issue = 8 | pages = 4332–4345 | date = August 2011 | pmid = 21562678 | doi = 10.1039/C1CS15053G }}</ref><ref>{{cite web|url=http://www.bio-itworld.com/columns/feature-article/conquering-infinity-with--chemical-genetics--2003-02-10t000000-6-1938/?terms=Infinity+Schreiber|title=Conquering Infinity with Chemical Genetics| vauthors = Branca M |date=Feb 2003|work=Bio IT World |access-date=2020-03-27|archive-date=2023-03-17|archive-url=https://web.archive.org/web/20230317183403/https://www.bio-itworld.com/columns/feature-article/conquering-infinity-with--chemical-genetics--2003-02-10t000000-6-1938/?terms=Infinity+Schreiber|url-status=dead}}</ref> The approach was first proposed by [[Tim Mitchison]] in 1994 in an opinion piece in the journal ''Chemistry & Biology'' entitled "Towards a pharmacological genetics".<ref>{{cite journal | vauthors = Mitchison TJ | title = Towards a pharmacological genetics | journal = Chemistry & Biology | volume = 1 | issue = 1 | pages = 3–6 | date = September 1994 | pmid = 9383364 | doi = 10.1016/1074-5521(94)90034-5 }}</ref>

== Method ==

Chemical genetic screens are performed using libraries of [[small molecule]]s that have known activities or simply diverse chemical structures. These screens can be done in a [[high-throughput screening|high-throughput]] mode, using 96 well-plates, where each well contains cells treated with a unique compound. In addition to cells, ''[[Xenopus]]'' or [[zebrafish]] embryos can also be screened in 96 well format where compounds are dissolved in the media in which embryos grow. Embryos are developed until the stage of interest and then the phenotype can be analyzed. Several concentrations can be tested in order to determine the toxic and the optimal concentrations.<ref>{{cite journal | vauthors = Tomlinson ML, Rejzek M, Fidock M, Field RA, Wheeler GN | title = Chemical genomics identifies compounds affecting Xenopus laevis pigment cell development | journal = Molecular BioSystems | volume = 5 | issue = 4 | pages = 376–384 | date = April 2009 | pmid = 19396374 | doi = 10.1039/B818695B }}</ref><ref>{{cite journal | vauthors = Kälin RE, Bänziger-Tobler NE, Detmar M, Brändli AW | title = An in vivo chemical library screen in Xenopus tadpoles reveals novel pathways involved in angiogenesis and lymphangiogenesis | journal = Blood | volume = 114 | issue = 5 | pages = 1110–1122 | date = July 2009 | pmid = 19478043 | pmc = 2721788 | doi = 10.1182/blood-2009-03-211771 }}</ref>

== Applications ==

Adding compounds to developing embryos allow comprehension of mechanism of action of drugs, their toxicity and developmental processes involving their targets. Chemical screens have been mostly performed on either wild type or transgenic ''[[Xenopus]]'' and [[zebrafish]] organisms as they produce a large amount of synchronized, fast-to-develop and transparent eggs easy to visually score.<ref>{{cite journal | vauthors = Taylor KL, Grant NJ, Temperley ND, Patton EE | title = Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads | journal = Cell Communication and Signaling | volume = 8 | issue = 1 | pages = 11 | date = June 2010 | pmid = 20540792 | pmc = 2912314 | doi = 10.1186/1478-811x-8-11 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ny A, Autiero M, Carmeliet P | title = Zebrafish and Xenopus tadpoles: small animal models to study angiogenesis and lymphangiogenesis | journal = Experimental Cell Research | volume = 312 | issue = 5 | pages = 684–693 | date = March 2006 | pmid = 16309670 | doi = 10.1016/j.yexcr.2005.10.018 | series = Special Issue on Angiogenesis }}</ref> The use of chemicals in developmental biology offers two main advantages. Firstly, it is easy to perform high-throughput screen using wide spectrum or specific target compounds and reveal important genes or pathways involved in developmental processes. Secondly, it allows narrowing the time of action of a particular gene.<ref>{{cite journal | vauthors = Tomlinson ML, Guan P, Morris RJ, Fidock MD, Rejzek M, Garcia-Morales C, Field RA, Wheeler GN | title = A chemical genomic approach identifies matrix metalloproteinases as playing an essential and specific role in Xenopus melanophore migration | journal = Chemistry & Biology | volume = 16 | issue = 1 | pages = 93–104 | date = January 2009 | pmid = 19171309 | doi = 10.1016/j.chembiol.2008.12.005 | doi-access = free }}</ref> It can also be used as a tool in drug development to test toxicity in whole organism. Procedures such as FETAX (Frog Embryo Teratogenesis Assay – Xenopus) are being developed to implement chemical screenings to test toxicity.<ref>{{cite journal | vauthors = Hu L, Zhu J, Rotchell JM, Wu L, Gao J, Shi H | title = Use of the enhanced frog embryo teratogenesis assay-Xenopus (FETAX) to determine chemically-induced phenotypic effects | journal = The Science of the Total Environment | volume = 508 | pages = 258–265 | date = March 2015 | pmid = 25481254 | doi = 10.1016/j.scitotenv.2014.11.086 | bibcode = 2015ScTEn.508..258H }}</ref> Zebrafish and ''Xenopus'' embryos have also been used to identify new drugs targeting a particular gene of interest.<ref>{{cite journal | vauthors = Molina G, Vogt A, Bakan A, Dai W, Queiroz de Oliveira P, Znosko W, Smithgall TE, Bahar I, Lazo JS, Day BW, Tsang M | title = Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages | journal = Nature Chemical Biology | volume = 5 | issue = 9 | pages = 680–687 | date = September 2009 | pmid = 19578332 | pmc = 2771339 | doi = 10.1038/nchembio.190 }}</ref>

== See also ==
* [[Chemoproteomics]]
*[[Chemical biology]]
* [[Chemogenomics]]

== References ==
{{Reflist|33em}}

[[Category:Genetics]]

Chemical genetics - История изменений

Admin: 1 версия импортирована

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