Kukhudzidwa kwa chitetezo chamthupi mu RDEB (2023)

Kafukufukuyu adapeza kuti maselo akhungu a RDEB ali kale ndi zosintha zomwe zingalole khansa kukula ndikufalikira pasanakhale khansa yapakhungu yodziwika. Kulandira chithandizo mwamsanga kuti muchepetse kusinthaku kungachititse kuti khansa yapakhungu isachitike kapena kuichedwetsa.
Zizindikiro za RDEB zomwe zimayamba chifukwa cha kutupa kwachilengedwe kwa khungu zimatha kuthandizidwa ndi mankhwala oletsa kutupa omwe amachepetsa zinthu zinazake pakhungu, makamaka zomwe zimatchedwa interleukin-1.

Zotsatira za kafukufukuyu zidasindikizidwa mu Seputembara 2023. Nkhani yonena za zopezeka kwa anthu wamba iliponso.

Wofufuza Wotsogolera: Dr Yanling Liao, Pulofesa Wothandizira wa Pediatrics.

Dr. Yanling Liao adamupeza Bachelor of Science mu Biology ku Xiamen University, PR China ndi PhD yake kuchokera ku Dipatimenti ya Biochemistry ku Albert Einstein College of Medicine, New York, kufufuza njira ya RNA transcriptional regulation. Anachita maphunziro ake apamwamba mu labotale ya Dr. Helen Blau ku Dipatimenti ya Immunology & Microbiology ku Stanford University School of Medicine, California, ndipo pambuyo pake adalowa mu labotale ya Dr. Mitchell Cairo ku Dipatimenti ya Pediatrics, Columbia University Medical Center, New York. Dr. Liao adakhala Pulofesa Wothandizira Kafukufuku wa Pediatrics mu 2011 ndi Pulofesa Wothandizira wa Pediatrics ku 2014 ku New York Medical College, kumene kafukufuku wake wamkulu wakhala akuyang'ana pa chitukuko cha preclinical cha stem cell ndi mapuloteni a RDEB.

Wofufuza-mmodzi: Pulofesa Mitchell Cairo, Wapampando Wothandizira wa dipatimenti ya Pediatrics & Pulofesa wa Pediatrics, Medicine, Pathology, Microbiology, Immunology, Cell Biology & Anatomy ku NYMC.

Pulofesa Mitchell Cairo pano ndi Wapampando Wothandizira ndi Pulofesa (wokhala nawo) mu dipatimenti ya Pediatrics ku New York Medical College (NYMC). Maudindo ake owonjezera aposachedwa akuphatikizapo kukhala Chief of the Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Program Director wa Adult & Pediatric BMT Program, Director of Childhood and Adolescent Cancer and Blood Disease Center, Medical and Scientific Director of the GMP Cellular and Tissue Engineering Laboratory ku Westchester Medical Center (WMC), Medical Director wa WMC Hematotherapy Program ndi Wapampando wa WMC Adult and Pediatric Cancer Program. Maudindo owonjezera a Dr. Cairo akuphatikizapo kukhala Pulofesa wa Zamankhwala, Pathology, Microbiology ndi Immunology ndi Cell Biology ndi Anatomy ndi Public Health ku NYMC.

"Zadziwika bwino kuti kutupa kosatha ndi fibrosis zimathandizira pakukula kwa squamous cell carcinoma mwa odwala omwe ali ndi RDEB. Kuyankha kotupa, komwe kuli chitetezo chachilengedwe m'thupi mwathu, kumayenera kuthetsedwa pambuyo poteteza matenda ndi / kapena kuvulala, komabe sikunathetsedwe kwa odwala omwe ali ndi RDEB. M'malo mwake, zimasanduka matenda osafunikira mwa odwalawa. Mwakutero, kufufuza kwathu kudzatithandiza kuzindikira momwe maselo oteteza thupi pakhungu amasinthira pakapita nthawi potengera kusintha kwa dermal microenvironment. Kafukufukuyu atithandiza kumvetsetsa momwe kutupa kwanthawi yayitali ndikuzindikiritsa zomwe mukufuna kuchiza kapena kupewa kutupa kosatha komanso fibrosis mwa odwala omwe ali ndi RDEB."

Dr Yanling Liao

Grant Title: Kuzindikiritsa njira zodzitetezera m'thupi komanso zosinthika zomwe zimagwirizanitsidwa ndi fibrosis m'zinyama za RDEB

Pali mitundu iwiri ya kutupa, yoyamba ndi tizilombo tating'onoting'ono (monga kukhalapo kwa mabakiteriya), ndipo ina imakhala yopanda tizilombo toyambitsa matenda, yomwe imatchedwanso kutupa kosabala. Chodziwika bwino cha kutupa kosabala ndikuti nthawi zambiri kungayambitse kutupa kosatha komanso fibrosis. Malingana ndi maphunziro athu oyambirira, ndizotheka kuti odwala omwe ali ndi RDEB akhoza kubadwa ndi kutupa kosabala komanso kusokonezeka ndi kutupa kwa tizilombo toyambitsa matenda chifukwa cha kusowa kwa Collagen 7. kuposa vuto ndi khungu ndi mucous nembanemba. Kutupa kosalekeza komanso kosasinthika ndiye kumabweretsa vuto lalikulu, fibrosis ndipo pamapeto pake zitha kulumikizidwa ndi chitukuko cha squamous cell carcinoma. Chifukwa chake ndikofunikira kumvetsetsa njira zoyambira zotupa izi. Maphunziro omwe aperekedwawo aphatikiza mtundu wa RDEB womwe ulibe COL7A1 kuti ufufuze kuti ndi mitundu yanji ya ma cell a chitetezo chamthupi omwe amalowa pakhungu m'malo osabala.

Gululo liwonanso zomwe ma siginecha a ma cell amathandizira kulowa kwawo, momwe amalumikizirana wina ndi mnzake komanso ndi chilengedwe chapakhungu. Kutengera zotsatirazi, afufuza ngati ma siginecha amatha kuyimitsidwa kapena kuchedwetsedwa kuti athetse kutupa kosatha komanso fibrosis.
Zinthu zamitundu iwiri ya kuyankha kwa chitetezo chamthupi (zobadwa mwachibadwa ndi zosinthika), zonse zawonetsedwa kuti zimagwira ntchito yofunika kuyambitsa fibrosis m'zigawo zambiri zamagulu monga mapapo ndi chiwindi. Komabe, gawo lawo pakutupa kosatha ndi fibrosis mu RDEB silikumvekabe.
Maphunziro omwe akufunsidwawo adzafufuza momwe mayankhidwe a chitetezo chamthupi amayendera komanso kulumikizana kwawo ndi chizindikiro chapakhungu kuti amvetsetse kupita patsogolo ndi kusintha kwa chitetezo chamthupi.
Tikuyembekeza kuti pozindikira njira zowonetsera, ntchitoyi idzawulula njira zomwe zimagwirizana ndi kutupa ndi fibrosis, kuzindikira zomwe zingatheke kuti alowemo mwamsanga ndi chitukuko cha mankhwala atsopano komanso othandiza kwambiri a chitetezo cha mthupi mu RDEB.

Kutupa ndi chitetezo chachilengedwe cha thupi ku matenda ndi/kapena kuvulala. Komabe, kafukufuku wambiri akuwonetsa kuti cutaneous squamous cell carcinomas mwa odwala omwe ali ndi RDEB amatuluka m'malo otupa kosalekeza. Khungu la odwala omwe ali ndi RDEB limalumikizidwa ndi zotupa zowopsa komanso ma colonization. Momwe mayankho otupa amasinthira kukhala vuto losafunikira kwa odwala omwe ali ndi RDEB sikudziwika bwino. Mu kafukufukuyu, tapeza kuti, ngakhale zotupa zisanachitike, ma cell akhungu amawonetsa kale zinthu zomwe zimathandizira kukula kwa chotupa ndi metastasis, zofanana ndi zomwe zimawonedwa pakhungu lomwe limakula. Zinthuzi zikuphatikizapo kusinthika kwa mphamvu (Anaerobic metabolism), proliferative epidermal cell, kupititsa patsogolo chitetezo cha mthupi komanso kuyambitsa, kutsegula kwa fibroblast, kupititsa patsogolo angiogenesis etc. Deta yathu yasonyeza kuti chotupa ichi chothandizira RDEB dermal niche (dermal microenvironment) chakhazikitsidwa chisanayambe. za kusintha kwa chotupa ndikuwonetsa kuti kulowererapo mwachangu kuti asinthe mawonekedwe a dermal microenvironment ndikofunikira kwa anthu omwe ali ndi RDEB, kuti mwina achedwetse kapena kupewa kukula kwa chotupa.

Tinayesanso oyimira osiyana a kutupa pakhungu ndipo tidazindikira kuti interleukin 1 (IL-1α) ngati chinthu chachikulu (cytokine) chomwe chidayambitsa mayankho otupa kuyambira pakubadwa ndikusunga kutupa kosatha ndi ma cytokines ena otupa (monga IL-6 ndi TNF). Tinatsimikiziranso zotsatira za IL-1α pakusintha ma phenotypes a RDEB fibroblasts. Kafukufuku wathu akuwonetsa kuti kuletsa kwa IL-1α, kapena kuphatikiza ndi zoletsa motsutsana ndi ma cytokines ena omwe adawonekera pakapita nthawi kuposa IL-1α, kumatha kukhala ngati mankhwala oletsa kutupa. The zotsatira za kafukufukuyu zasindikizidwa pa intaneti.

Phunziro lathu likuyang'ana pakumvetsetsa momwe kutupa kwamitundu ya RDEB mbewa. Tinayang'ana majini omwe amawonetsedwa m'maselo amtundu uliwonse (monga maselo a epidermal, maselo a khungu, maselo a chitetezo cha mthupi, maselo a mitsempha ndi maselo a mitsempha mkati mwa khungu) mu mbewa za RDEB ndikuziyerekeza ndi mbewa zathanzi. Tidapeza kuti ma cell onse asintha kagayidwe kachakudya kupita ku aerobic glycolysis, potengera chilengedwe cha dermal hypoxia (ochepa mpweya). Kupititsa patsogolo glycolysis ndi gawo lodziwika bwino la ma cell a khansa komanso chandamale cha chithandizo cha khansa. Timanena kuti hypoxia yochititsa chizindikiro ndi glycolysis ingakhalenso chandamale cha chithandizo chamankhwala mu RDEB. Tidapezanso mafotokozedwe apadera a jini kapena kuchuluka kwa ma cell mu RDEB omwe amakhudzana ndi kukula kwa RDEB. Kutengera kuchulukira kwazinthu zingapo zomwe zili mumayendedwe oyipa, titha kuwona kuti khungu la RDEB likuyesera kubweza kuwonongeka kwa minofu popanga malo opondereza chitetezo chamthupi kuti alimbikitse machiritso.

Komabe, izi zili pamtengo wochepetsera magwiridwe antchito a T cell (monga momwe ziwonetsedwera pakuwonjezeka kwa mawu a PD-1 pama cell T, omwe ndi njira yopewera chotupa) komanso chiwopsezo chakukula kwa khansa. Kumbali ina, izi zimatsegula njira yotsekera PD-1 kuti ilimbikitsenso ntchito ya T cell mu RDEB. Panalinso kutsegula kwa njira zowonetsera zosiyana poyankha kutupa. Tikuyesera kuzindikira zomwe zimayimira njira iliyonse komanso nthawi yomwe zinthuzo zimawonekera komanso / kapena kutha. Izi zidzatipatsa mipherezero yochizira. Pakalipano, chimodzi mwa zinthu zodalirika zomwe zingakhale chithandizo chamankhwala ndi interleukin (IL) -1a, yomwe mlingo wake unali wapamwamba kwambiri kuposa zina zonse zotupa pa mwana wakhanda ndipo anapitiriza kukula ndi zaka. Ndichizindikiro chowopsa mu RDEB koyambirira komwe kumayambitsa zotupa zonse zotsatirazi. Chizindikiro china chowopsa chikhoza kukhala chitetezo chamthupi chotchedwa 3 (C3). Izi zidadziwika mumadzi am'matuza a mbewa za RDEB ndipo zidawonetsedwa kwambiri mumagulu ena a fibroblast (dermal cell) omwe amagawana zinthu zofanana ndi zomwe zingapezeke mu ma fibroblasts okhudzana ndi khansa.

Maphunziro athu amtsogolo adzawona zotsatira za kutsekereza IL1a ndi C3 pakupondereza kutupa mu RDEB. (Kuchokera ku lipoti la 2022.)