Part 2|Genetic Variation Implicates Plasma Angiopoietin-2 Hauv Kev Loj Hlob Ntawm Kev Mob Raum Raum Mob Sub-phenotypes

Nyem qhov no rau ntu 1

Yog xav paub ntxiv thov hu rau emily.li@wecistanche.com

Cistanche tuaj yeem txhim kho lub raum ua haujlwm

Kev sib tham

Kev tshawb nrhiav cov noob raug cuam tshuam hauv AKI tau cuam tshuam los ntawm heterogeneity nyob rau hauv kev kho mob phenotype. SivAKIsub-phenotypes, peb tau tshawb pom tias cov noob caj noob ces nyob ze ntawm ANGPT2 noob, rs2920656, tiv thaiv kev txhim kho ntawm AKI-SP2. Kev txheeb xyuas qhov tseeb qhia tau hais tias plasma ANG-2 concentrations mediated 41.5 feem pua ​​​​ntawm kev sib txuas caj ces ntawm rs2920656 thiabAKI-SP2txaus ntshai nyob rau hauv cov ntsiab lus ntawm cov poj koob yawm txwv nyob sab Europe. Tsis tas li ntawd, cov kev sim hauv vitro tau pom tias qhov me me ntawm rs2920656 tuaj yeem ua rau qis dua ANG-2 protein tso tawm los ntawmtib neeg lub raum endothelial hlwb. Tsis tas li ntawd, plasma ANG-2 yog qhov tsawg kawg nkaus tshem tawm, tawm tswv yim tias plasma ANG-2 nce siab yuav tsis zoo li tshwm sim los ntawmraumraug mob. Zuag qhia tag nrho, cov kev tshawb pom no muab.

Cov pov thawj tias plasma ANG-2 ua lub luag haujlwm ntawm tus tswv tsev cov lus teb rau kev mob hnyav ua rau AKI-SP2. Kev siv zog rau lub hom phiaj Ang-Tie2 axis yuav txwv tsis pub AKI qhov hnyav thiab ua rau cov txiaj ntsig tsis zoo [35]. Cov noob ANPT2 yog 100 feem pua ​​​​zes hauv microcephalin (MCPH1) noob. Kev hloov pauv hauv MCPH1 noob tau cuam tshuam nrog cov kab mob ntawm neurogenesis thiab lub raum cell carcinoma [36]. Peb tau pom tias rs2920656 yog qhov sib txawv intronic hauv MCPH1 uas tswj cov ntshav ANG-2 concentrations. Cov kev tshawb fawb yav dhau los tau txheeb xyuas cov caj ces txawv hauv MCPH1 [37] thiab ANGPT2 [38] uas cuam tshuam nrog ANG-2 concentrations. Nws kuj tseem pom tau tias rs2920656 cuam tshuam MCPH1 kev qhia. Txawm li cas los xij, rau peb txoj kev paub, tsis muaj lub luag haujlwm rau MCPH1 hauv qhov mob hnyav lossis mob ntevmob raumlossis raug mob vascular tau piav qhia. Hauv qhov sib piv, ntau qhov kev tshawb fawb ua ntej thiab kho mob tau pom lub luag haujlwm tseem ceeb ntawm plasma ANG-2 hauv kev txhim kho AKI [16, 39, 40].

Ntau cov ntawv tshaj tawm tau cuam tshuam cov plasma biomarkers ntawm endothelial muaj nuj nqi hauv pathophysiology ntawm AKI [39, 41, 42]. ANG-1 thiab -2 yog vascular endothelial kev loj hlob yam tseem ceeb uas ob leeg khi rau endothelial tyrosine kinase receptor (Tie-2) tab sis muaj cov ntsiab lus nyob ntawm cov dej num [43]. ANG-1 raug tso tawm los ntawm pericytes thiab platelets thiab yog ib qho agonist rau Tie-2 receptor. ANG-1 yog tiv thaiv los ntawm stabilizing lub endothelium thiab tiv thaiv microcirculatory capillary leakage, ib qho cim ntawm AKI [44]. Hauv qhov sib piv, ANG-2 feem ntau ua raws li tus antagonist rau Tie-2 receptor thiab txhawb nqa endothelial permeability [45] thiab o [46, 47]. ANGPT2 noob encodes rau circulating ANG{18}}, uas yog tso tawm los ntawm endothelial hlwb thaum lub sij hawm inflammatory stimulus. Cov kev tshawb fawb tsiaj tau pom tias inhibition ntawm ANG-2 khi, augmenting ANG-1 concentrations [41, 44], lossis ua kom Tie-2 [46] txo qis endothelial leak thiab tiv thaiv AKI. Ua ke cov kev tshawb fawb no cuam tshuam txog lub luag haujlwm ntawm ANG-Tie2 axis hauv AKI. Ntawm no peb qhia txog kev tswj hwm genomic ntawm plasma ANG-2 ua lwm yam uas txhawb nqa lub luag haujlwm ntawm ANG-2 hauv kev txhim kho cov qauv hnyav ntawm AKI, AKI-SP2.

Kev sib raug zoo ntawm plasma ANG-2 thiab kev txhim kho ntawm AKI-SP2 ua rau cov lus nug ntawm seb ANG-2 puas zoo ib yam li creatinine: lim los ntawmraumthiab qib siab tsuas yog qhov cuam tshuam ntawm kev txo lub raum pom. Txhawm rau ua kom pom tias cov ntshav ANG-2 cov ntshav siab tsis yog ib qho cim xwb tab sis ua rau muaj kev loj hlob ntawm AKI hnyav, peb muab ob kab pov thawj. Ua ntej, siv kev tshuaj ntsuam genetic causal inference, peb tau pom tias kev hloov pauv caj ces nyob ze ntawm ANGPT2 noob yog txuam nrog ANG-2 plasma concentrations thiab kev loj hlob ntawm AKI-SP2. Thib ob, tsis zoo li creatinine (113 Da), ANG-2 (57,000 Da) yog ib qho loj molecule uas tsis zoo li yuav tau lim dej tsis tu ncua ntawm glomerulus. Hauv cov neeg mob hnyav, peb tau pom tias lub raum tshem tawm tsawg kawg ntawm ANG-2. Yog li, qhov nce hauv ntshav ANG-2 qhov siab tsis zoo yuav yog vim qhov sib txawv ntawm lub raum pom thiab, hloov pauv, tuaj yeem koom nrog hauv pathophysiology ntawm AKI hauv cov neeg mob hnyav.

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias cov kab mob sib txawv ntawm ib tus neeg yuav muaj qhov cuam tshuam me me rau kev txhim kho kab mob vim tias AKI yuav yog tus kab mob polygenic. Lub zog ntawm qhov kev tshuaj ntsuam no yog kev txheeb xyuas cov kab mob sib txawv uas txhawb nqa ANG{{0}} ua qhov laj thawj hauv kev txhim kho AKI. Txawm tias muaj ntau qhov sib txawv nrog qhov loj me me muab lub sijhawm rau kev tshawb nrhiav txog txoj hauv kev tshiab uas muaj peev xwm siv tshuaj ntsuam genetic tshuaj. Piv txwv li, kab mob plawv, zoo ib yam li AKI, yog ib qho polygenic zoo nrog ntau yam kab mob sib txawv ntawm txhua tus piav qhia txog me me ntawm qhov kev pheej hmoo. Txawm li cas los xij, peb SNPs uas tau piav qhia tsuas yog 0.4 mus rau 2 feem pua ​​​​ntawm qhov sib txawv ntawm c-reactive protein ntau tau tso cai rau kev txiav txim siab tias c-reactive protein tsis yog qhov ua rau muaj kab mob ischemic vascular [48], thiab cov kev tshawb pom no tau lees paub hauv cov kev tshawb fawb tom ntej. [49].

Peb txoj haujlwm muaj ob peb lub zog. Ua ntej, peb siv AKI sub-phenotypes los ua kom muaj tseeb hauv cov ntsiab lus phenotype thiab ua kom pom qhov loj me kom pom cov noob caj noob ces. Qhov thib ob, kev soj ntsuam kev tshawb fawb pom tau tias 41.5 feem pua ​​​​ntawm rs2920656-kev pheej hmoo cuam tshuam rau kev tsim AKI-SP2 yog piav qhia los ntawm plasma ANG-2 qib. Qhov no muab cov ntaub ntawv pov thawj kho mob, txhawm rau txhim kho kev ua haujlwm los ntawm kev tshawb fawb tsiaj, qhov kev hloov pauv ntawm plasma ANG-2 cov ntsiab lus tuaj yeem txhim kho cov txiaj ntsig ntawm kev mob hnyav-txuas nrog AKI. Thib peb, txhawm rau suav rau qhov muaj peev xwm ua rau tsis txaus ntseeg thiab txuas Ang-2 ntau lawm tshwj xeeb rauraumcov hlwb endothelial, peb ua tiav cov kev sim hauv vitro siv HKMECs. Plaub, siv cov ICU tshwj xeeb nrog cov qauv sau cov zis thiab ua ntej thiab tom qab kuaj ntshav, peb muaj peev xwm ua kom pom tias tsawg kawg ntawm cov ntshav ANG-2 raug lim los ntawmraum. Yog li, lub koom haum muaj zog ntawm ANG-2 nrograum tshwj xeebCov txiaj ntsig zoo yuav tsis ua rau muaj kev ntxhov siab los ntawm cov teeb meem ntawm kev thim rov qab.

Peb txoj kev kawm muaj kev txwv. Peb tus qauv loj kuj me me. Txawm li cas los xij, peb qhov kev txheeb xyuas qhov zoo (AKI-SP2) tau tso cai rau peb txheeb xyuas cov caj ces nrog rau cov neeg mob hnyav nrog AKI. Thib ob, kev tshuaj ntsuam xyuas tau txwv rau cov neeg mob ntawm cov poj koob yawm txwv nyob sab Europe txhawm rau txo qis cov tshuaj tiv thaiv kab mob, ua kom muaj zog, thiab vim qhov sib txawv ntawm qhov sib txawv ntawm cov haiv neeg keeb kwm. Kev ua haujlwm yav tom ntej tau lees paub los kawm lwm haiv neeg los txiav txim siab seb qhov kev hloov pauv ntawm cov genomic zoo sib xws cuam tshuam rau plasma ANG-2 concentrations. Thib peb, thaum muaj qhov sib txawv hauv qis ANG-2 kev ntsuas hauv PTECs nrog cov me me, cov txiaj ntsig tsis tseem ceeb. Txawm li cas los xij, tib neeg cov qauv yog qhov nyuaj kom tau txais, thiab txawm tias muaj cov qauv me me peb pom cov kev taw qhia zoo ib yam. Thib plaub, vim muaj qhov tshwj xeeb ntawm cov ntaub ntawv no, peb tsis tuaj yeem nrhiav cov neeg mob zoo sib xws los luam peb cov kev tshawb pom. Peb cov ntaub ntawv suav nrog cov neeg mob zoo phenotyped nrog AKI, nrog cov ntaub ntawv genomic, plasma, thiab cov ntaub ntawv kho mob. Txawm li cas los xij, nyob rau hauv plaub tus neeg suav nrog hauv iSPAAR muaj kev coj ua zoo ib yam ntawm rs2920656 thiab kev txhim kho ntawm AKI-SP2. Kev ua haujlwm yav tom ntej tau lees paub kom nkag siab txog qhov cuam tshuam ntawm rs2920656 ntawm kev txhim kho sub-phenotype thiab AKI cov txiaj ntsig tshwj xeeb hauv kev kho mob.

Xaus

Hauv cov ntsiab lus, peb tau txheeb xyuas qhov sib txawv ntawm cov noob caj noob ces nyob ze ntawm ANGPT2 cov noob uas cuam tshuam nrog ntshav ANG-2 ntau thiab kev loj hlob ntawm AKI-SP2 ntawm cov neeg mob hnyav. Peb kuj tau sim lub koom haum no los ntawm kev kawm tiav hauv HKMECs. Peb qhov kev tshawb pom qhia tias plasma ANG-2 ua lub luag haujlwm tseem ceeb hauv kev txhim kho AKI-SP2 thiab ntseeg tias kev siv zog los tsom rau Ang-Tie2 axis tuaj yeem tiv thaiv kev txhim kho ntawm cov txiaj ntsig tsis zoo.

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