Isifundo esitsha sokugcina imithambo yakho icocekile

Ukuhlaziya inkqubo ecothayo njengoko sikhula kunokukhusela kwi-atherosclerosis, eyona nto ibangela ukuhlaselwa yintliziyo kunye nokubetha. Kwiziphumo ezipapashwe kwi-intanethi namhlanje kwiiNkqubo ze-National Academy of Sciences (PNAS), izazinzulu zase-Albert Einstein College of Medicine ekhokelwa ngu-Ana Maria Cuervo, MD, Ph.D., yanciphisa ngempumelelo i-plaque yokunciphisa umthambo kwiimpuku ezinokuthi ziphuhlise ezo izilonda. Abaphandi bakwenza oko ngokunyusa i-chaperone-mediated autophagy (CMA), inkqubo yeselula yokugcina indlu eyafunyanwa nguDkt Cuervo kwi-1993 kwaye yaqanjwa ngo-2000. 

“Kolu phando siye sabonisa ukuba sifuna iCMA ukuze ikhuseleke kwi<em>atherosclerosis, ethi ibe qatha ize iqhubele phambili xa iCMA isihla—into eyenzekayo xa abantu bebadala,” watsho uGqr. , uRobert noRenée Belfer uSihlalo weSifundo se-Neurodeergenerative Diseases, kunye no-co-director weZiko loPhando lokuguga e-Einstein. "Kodwa ngokulinganayo, sibonakalise ukuba ukonyuka komsebenzi we-CMA kunokuba sisicwangciso esisebenzayo sokunqanda i-atherosclerosis kunye nokumisa ukuqhubeka kwayo."

I-CV yeCMA enomtsalane

I-CMA igcina iiseli zisebenza ngokuqhelekileyo ngokuthoba ngokukhetha iiproteni ezininzi eziqulathwe ziiseli. Kwi-CMA, iiprotheyini ezikhethekileyo "ze-chaperone" zibophelela kwiiprotheyini kwi-cytoplasm kwaye zibakhokele kwizakhiwo zeselula ezizaliswe yi-enzyme ebizwa ngokuba yi-lysosomes ukuba igaywe kwaye isetyenziswe kwakhona. UDkt. Cuervo uye wachaza abaninzi abadlali be-molecular ababandakanyekayo kwi-CMA kwaye babonisa ukuba i-CMA, ngokuchithwa kwayo ngexesha elifanelekileyo leeprotheni eziphambili, ilawula iinkqubo ezininzi ze-intracellular ezibandakanya i-glucose kunye ne-lipid metabolism, i-circadian rhythms kunye nokulungiswa kwe-DNA. Kwakhona wafumanisa ukuba i-CMA ephazamisekile ivumela iiprotheni ezonakalisiweyo ukuba ziqokelele kumanqanaba anetyhefu, igalelo ekugugeni kwaye-xa i-buildup enetyhefu ivela kwiiseli ze-nerve-kwizifo ze-neurodeergenerative ezibandakanya i-Parkinson's, i-Alzheimer's, kunye nesifo sikaHuntington.

Impumelelo kaGqr. Cuervo yamkelwa ngo-2019 xa wonyulwa kwiNational Academy of Sciences (NAS). Ngo-1996, i-NAS yaqala ukumema amalungu ayo asanda kunyulwa ukuba angenise iNqaku elikhethekileyo lokuQalisa kwi-PNAS eliza kugxininisa igalelo lenzululwazi lelungu. Ngenxa yolibaziseko olunxulumene nobhubhane we-COVID-19, iphepha lanamhlanje ngendima yokhuselo ye-CMA ngokuchasene ne-atherosclerosis liphepha lokuqala likaGqr. Cuervo le-PNAS kwaye longeza kumzimba wakhe womsebenzi ngokubaluleka kwe-CMA.

Ukulwa Ngokuchasene nePlaque

Isifo seCardiovascular (CVD) sesona sizathu siphambili sokusweleka kwihlabathi, ngaphezulu kwe-80% ye-CVD yokusweleka ngenxa yokuhlaselwa sisifo sentliziyo kunye nokubetha. I-CVD, ngokuqhelekileyo, idla ngokuhambelana ne-atherosclerosis: i-buildup of plaque (izinto ezinamathele eziqulethwe ngamafutha, i-cholesterol, i-calcium, kunye nezinye izinto) ngaphakathi kweendonga ze-arteries. Ukuqokelelana kwe-plaque kwenza lukhuni kwaye kucuthe imithambo, ithintele ekuhambiseni igazi elineoksijini kwisihlunu sentliziyo (ekhokelela ekuhlaselweni kwentliziyo), ingqondo (istroke), nakuwo wonke umzimba.

Ukuphanda indima ye-CMA kwi-atherosclerosis, uDkt Cuervo kunye noogxa bakhuthaza i-atherosclerosis kwiimpuku ngokuzondla ukutya okunamafutha aseNtshona kwiiveki ze-12 kunye nokubeka iliso kwi-CMA kwi-aortas echaphazelekayo ye-plaque yezilwanyana. Umsebenzi we-CMA wanda ekuqaleni ekuphenduleni umngeni wokutya; emva kweeveki ze-12, nangona kunjalo, i-plaque buildup yayibalulekile, kwaye akukho msebenzi we-CMA unokubonwa kwiintlobo ezimbini zeeseli-macrophages kunye neeseli ze-arterial smooth muscle-ezaziwa ngokungasebenzi kakuhle kwi-atherosclerosis, ekhokelela ekuqulunqweni kwe-plaque ngaphakathi kwemithambo.

"I-CMA ibonakala ibaluleke kakhulu ekukhuseleni i-macrophages kunye neeseli ze-muscle ezibushelelezi-ezibanceda ukuba basebenze ngokuqhelekileyo nangona ukutya kwe-pro-atherosclerotic-ubuncinane okwethutyana, de umsebenzi wabo we-CMA uphelile," kusho uDkt Cuervo. Uqaphele ukuba ukondla ukutya okunamafutha aphezulu kwiimpuku ezinqongopheleyo kumsebenzi we-CMA kuvelisa ubungqina obunamandla bokubaluleka kwe-CMA: iiplakhi eziphantse zibe ngama-40% ezinkulu kunezo zilawula izilwanyana ezazikukutya okunamafutha aphezulu.

Yeempuku kwakunye naMadoda

Abaphandi bafumene ubungqina bokuba umsebenzi obuthathaka we-CMA uhambelana ne-atherosclerosis nasebantwini. Ezinye izigulana ezikhe zabethwa sistrowuku zenza utyando, olubizwa ngokuba yi-carotid endarterectomy, olususa amacandelo achaphazelekileyo kwi-plaque yemithambo ye-carotid ukunciphisa umngcipheko we-stroke yesibini. UDkt Cuervo kunye noogxa bakhe bahlalutya umsebenzi we-CMA kumacandelo e-carotid artery evela kwizigulane ze-62 zokuqala ezilandelwayo iminyaka emithathu emva kokuhlinzwa kwabo.

"Ezo zigulana ezinamazinga aphezulu e-CMA emva kokubetha kwazo kokuqala azizange zifumane okwesibini, ngelixa ukubetha okwesibini kwenzeka phantse kuzo zonke izigulane ezinomsebenzi ophantsi we-CMA," kusho uDkt Cuervo. "Oku kuphakamisa ukuba inqanaba lomsebenzi wakho we-CMA emva kwe-endarterectomy unokunceda ukuqikelela umngcipheko wakho we-stroke yesibini kunye nokukhokela unyango, ngakumbi kubantu abane-CMA ephantsi."

Ukuvula i-CMA, ukuTyunya i-Atherosclerosis

Uphononongo lolokuqala ukubonisa ukuba ukuguqula i-CMA inokuba yindlela esebenzayo yokuthintela i-atherosclerosis ukuba ibe nzima okanye iqhubele phambili. Abaphandi bezofuzo "balawulwa" i-CMA kwiigundane ezondliwa i-pro-atherosclerotic, i-fat high-fat Western diet kwaye kamva bathelekisa kunye neegundane zokulawula ezondla ukutya okufanayo kwiiveki ze-12. Iimpuku ze-CMA-zonyuswa ziye zaphucula kakhulu iiprofayili zelipid yegazi, kunye namanqanaba ancitshisiweyo e-cholesterol xa kuthelekiswa neempuku zolawulo. Izilonda ze-Plaque ezenziwe kwiigundane eziguqulwe ngokwemfuza zazincinci kakhulu kwaye zincinci ngobunzima xa kuthelekiswa namacwecwe kwiigundane zokulawula. Ngethamsanqa, abantu abayi kudinga utshintsho lwemfuzo ukuze bazuze koku kufunyaniswayo.

"Abalingane bam kunye nam siye savelisa i-compounds yeziyobisi eziye zabonisa isithembiso sokunyusa ngokukhuselekileyo nangempumelelo umsebenzi we-CMA kwiindawo ezininzi ze-mouse kunye neeseli ezenziwe ngabantu," kusho uDkt Cuervo. U-Einstein uye wafaka ipropathi yobukrelekrele kule teknoloji isisiseko.

Iphepha le-PNAS linesihloko esithi "Indima ekhuselayo ye-chaperone-mediated autophagy ngokuchasene ne-atherosclerosis." Abanye ababhali be-Einstein nguJulio Madrigal-Matute, Ph.D., Dario F. Riascos-Bernal, Antonio Diaz, MD, Ph.D., Inmaculada Tasset, Ph.D., Adrian Martin-Segura, Ph.D., Susmita Kaushik, Ph.D., Simoni Tiano, MD, Matthieu Bourdenx, Ph.D., Gregory J. Krause, MS, Nicholas Sibinga, MD, Fernando Macian, MD, Ph.D., kunye noRajat Singh, MD Elinye iphepha umbhali osebenzisana naye nguJudith C. Sluimer, Ph.D., weZiko lezoNyango leYunivesithi yaseMaastricht eNetherlands kunye neYunivesithi yase-Edinburgh eUnited Kingdom.