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Manawa o ka make: Pono ʻenehana hou no ka pololei loa

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He mea paʻakikī loa ka haʻi ʻana i ka wā i make ai ke kelepona lolo. ʻO nā neurons i ʻike ʻole ʻia a ʻāpana ʻia ma lalo o ka microscope hiki ke hoʻomau i kahi ʻano limbo ola a make paha no nā lā, a hoʻomaka koke kekahi e hōʻailona hou ma hope o ka ʻike ʻole ʻana.

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No nā mea noiʻi e aʻo nei i ka neurodegeneration, ʻo kēia nele o ka ʻōlelo "manawa o ka make" pololei no nā neurons he mea paʻakikī ke kuhikuhi i nā mea e alakaʻi ai i ka make cell a me ka nānā ʻana i nā lāʻau lapaʻau e hoʻopakele ai i nā cell kahiko mai ka make.              

I kēia manawa, ua hoʻomohala nā mea noiʻi ma Gladstone Institutes i kahi ʻenehana hou e hiki ai iā lākou ke hahai i nā tausani o nā cell i ka manawa a hoʻoholo i ka manawa kūpono o ka make no kēlā me kēia cell i ka hui. Ua hōʻike ka hui, i loko o kahi pepa i paʻi ʻia ma ka puke pai Nature Communications, e hana ana ke ala i loko o nā ʻiole a me nā pūnaewele kanaka a i loko o ka iʻa zebrafish ola, a hiki ke hoʻohana ʻia e hahai i nā cell i kahi manawa o nā pule a i nā mahina.

"He mea koʻikoʻi ka loaʻa ʻana o ka manawa kūpono o ka make no ka wehe ʻana i ke kumu a me ka hopena i nā maʻi neurodegenerative," wahi a Steve Finkbeiner, MD, PhD, ka luna o ka Center for Systems and Therapeutics ma Gladstone a me ka mea kākau kiʻekiʻe o nā haʻawina hou ʻelua. "E ʻae iā mākou e noʻonoʻo i nā kumu e hoʻopiʻi pololei ai i ka make cell, he mea kū ʻole, a ʻo ia paha nā mea hana e hoʻolōʻihi i ka make."

I loko o kahi pepa hoa i paʻi ʻia ma ka puke pai Science Advances, ua hui nā mea noiʻi i ka ʻenehana sensor cell me kahi ala e aʻo ai i ka mīkini, e aʻo ana i ke kamepiula pehea e hoʻokaʻawale ai i nā cell ola a me nā mea make he 100 mau manawa wikiwiki a ʻoi aku ka pololei ma mua o ke kanaka.

"Ua lawe nā haumāna kulanui i mau mahina e kālailai i kēia ʻano ʻikepili ma ka lima, a ʻo kā mākou ʻōnaehana hou ua aneane hikiwawe - ʻoi aku ka wikiwiki o ka holo ʻana ma mua o ka hiki iā mākou ke kiʻi i nā kiʻi hou ma ka microscope," wahi a Jeremy Linsley, PhD, he alakaʻi papahana ʻepekema ma Finkbeiner's. lab a me ka mea kākau mua o nā pepa hou ʻelua.

Ke aʻo ʻana i kahi sensor kahiko i nā hoʻopunipuni hou

Ke make nā pūnaewele—no ke kumu a i ʻole ke ʻano hana—e lilo lākou i ʻāpana a me ka emi ʻana o ko lākou mau membrane. Akā, ʻo kēia kaʻina hana hoʻohaʻahaʻa e paʻakikī i ka poʻe ʻepekema ke hoʻokaʻawale i waena o nā cell i hala lōʻihi i ka hana ʻana, nā mea maʻi a make, a me nā mea olakino.

Hoʻohana maʻamau ka poʻe noiʻi i nā hōʻailona fluorescent a i ʻole nā ​​​​mea pena e hahai i nā maʻi maʻi me kahi microscope i ka manawa a hoʻāʻo e ʻike i kahi o lākou i loko o kēia kaʻina hana hoʻohaʻahaʻa. Ua hoʻomohala ʻia ka nui o nā mea pena, nā ʻili, a me nā lepili e hoʻokaʻawale i nā cell i make mua mai nā mea e ola nei, akā hana pinepine lākou i nā manawa pōkole ma mua o ka mae ʻana a hiki ke lilo i mea ʻona i nā cell ke hoʻohana ʻia.

"Makemake maoli mākou i kahi hōʻailona e mau ana no ke ola holoʻokoʻa o ke kelepona—ʻaʻole he mau hola wale nō—a laila hāʻawi i kahi hōʻailona maopopo ma hope o ka manawa kikoʻī e make ai ke kelepona," wahi a Linsley.

Ua koho ʻo Linsley, Finkbeiner, a me kā lākou mau hoa hana i nā mea ʻike calcium, i hana mua ʻia e nānā i nā pae o ka calcium i loko o kahi keena. I ka make ʻana o ke kelepona a lilo nā membrane i leaky, ʻo ka hopena ʻaoʻao ʻo ia ka holo wikiwiki ʻana o ka calcium i loko o ka cytosol wai o ka cell, kahi haʻahaʻa haʻahaʻa o ka calcium.

No laila, ua ʻenehana ʻo Linsley i nā mea ʻike calcium e noho i loko o ka cytosol, kahi e lele ai lākou i ka wā i piʻi ai nā kiʻekiʻe calcium i kahi pae e hōʻike ana i ka make cell. Hiki ke hoʻokomo ʻia nā mea ʻike hou, i kapa ʻia ʻo genetically encoded death indicator (GEDI, i ʻōlelo ʻia e like me Jedi ma Star Wars), i loko o kēlā me kēia ʻano cell a hōʻailona ke ola a make paha ka cell i ke ola holoʻokoʻa o ka cell.

No ka hoʻāʻo ʻana i ka pono o nā sensor i hoʻolālā hou ʻia, ua kau ka hui i nā pūʻulu nui o nā neurons-ʻo kēlā me kēia me GEDI-ma lalo o ka microscope. Ma hope o ka ʻike ʻana i ʻoi aku ma mua o hoʻokahi miliona mau pūnaewele, i kekahi mau hihia e pili ana i ka neurodegeneration a ma nā mea ʻē aʻe i ʻike ʻia i nā pūhui ʻawaʻawa, ua ʻike nā mea noiʻi ua ʻoi aku ka pololei o ka sensor GEDI ma mua o nā hōʻailona make cell ʻē aʻe: ʻaʻohe hihia hoʻokahi kahi i loaʻa ai ka sensor. ho'ā 'ia a ola ke kelepona. Ma waho aʻe o kēlā pololei, ua ʻike pū ʻo GEDI i ka make cell ma kahi mua ma mua o nā ʻano hana mua - kokoke i ka "point of no return" no ka make cell.

"ʻAe kēia iā ʻoe e hoʻokaʻawale i nā sela ola a me nā mea make ma ke ʻano i hiki ʻole ma mua," wahi a Linsley.

ʻIke ʻana i ka make kanaka kiʻekiʻe

Ua haʻi aku ʻo Linsley iā GEDI i kona kaikunāne—ʻo Drew Linsley, PhD, he kumu aʻoaʻo kōkua ma ke Kulanui ʻo Brown nona ka loea i ka hoʻohana ʻana i ka naʻauao kūlohelohe i ka ʻikepili koolaola nui. Ua manaʻo kona kaikunāne e hoʻohana ka poʻe noiʻi i ka mea ʻike, i hui pū ʻia me kahi ala aʻo mīkini, e aʻo i kahi ʻōnaehana kamepiula e ʻike i nā cell lolo ola a make ma muli o ke ʻano o ke kelepona.

Hoʻohui ka hui i nā hualoaʻa mai ka mea ʻike hou me ka ʻikepili fluorescence maʻamau ma nā neurons like, a ua aʻo lākou i kahi ʻano kamepiula, i kapa ʻia ʻo BO-CNN, e ʻike i nā ʻano fluorescence maʻamau e pili ana i ke ʻano o nā cell e make ana. ʻO ke kumu hoʻohālike, nā kaikunāne Linsley i hōʻike ai, he 96 pakeneka pololei a ʻoi aku ka maikaʻi ma mua o ka mea hiki ke hana i nā mea nānā kanaka, a ʻoi aku ma mua o 100 mau manawa ʻoi aku ka wikiwiki ma mua o nā ala mua o ka hoʻokaʻawale ʻana i nā cell ola a me nā mea make.

“No kekahi mau ʻano kelepona, he mea paʻakikī loa i ke kanaka ke ʻimi i ke ola a i ʻole ka make o ke kelepona—akā, ua hiki i kā mākou kamepiula kamepiula, ma ke aʻo ʻana mai GEDI, ua hiki ke hoʻokaʻawale iā lākou ma muli o nā ʻāpana o nā kiʻi a mākou i ʻike ʻole ai ma mua. Ua kōkua lākou i ka hoʻokaʻawale ʻana i nā sela ola a me nā mea make," wahi a Jeremy Linsley.

E ʻae ʻo GEDI a me BO-CNN i ka poʻe noiʻi e hana i nā haʻawina hou, kiʻekiʻe-throughput e ʻike ai i ka wā a me kahi e make ai nā ʻōpū o ka lolo - kahi hopena koʻikoʻi no kekahi o nā maʻi koʻikoʻi. Hiki iā lākou ke nānā i nā lāʻau lapaʻau no ko lākou hiki ke hoʻopaneʻe a pale i ka make cell i nā maʻi neurodegenerative. A i ʻole, i ka hihia o ka maʻi kanesa, hiki iā lākou ke ʻimi i nā lāʻau e wikiwiki ai ka make o nā maʻi maʻi.

"ʻO kēia mau ʻenehana nā mea hoʻololi pāʻani i ko mākou hiki ke hoʻomaopopo i kahi, i ka manawa, a me ke kumu o ka make i loko o nā cell," wahi a Finkbeiner. "No ka manawa mua, hiki iā mākou ke hoʻohana maoli i ka wikiwiki a me ka unahi i hāʻawi ʻia e nā holomua i ka microscopy kōkua robot e ʻike pono i ka make cell, a hana maikaʻi ma mua o ka manawa o ka make. Manaʻo mākou hiki i kēia ke alakaʻi i nā therapeutics kikoʻī no nā maʻi neurodegenerative he nui i hiki ʻole ke hoʻōla ʻia.

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