Shigar da tsarin rigakafi a cikin RDEB (2023)

Wannan bincike ya gano cewa ƙwayoyin fata na RDEB sun riga sun sami canje-canje waɗanda zasu ba da damar ciwon daji ya girma da kuma yadawa kafin a sami ciwon daji na fata. Magani da wuri don rage waɗannan canje-canje na iya hana ciwon daji na fata faruwa ko rage ta.
Alamun RDEB da ke haifar da tsarin fata na kumburi na iya zama taimako ta hanyar magungunan ƙwayoyin cuta waɗanda ke rage takamaiman abubuwa a cikin fata, musamman wanda ake kira interleukin-1.

An buga sakamakon wannan binciken a cikin Satumba 2023. Labari game da sakamakon binciken ga masu sauraro yana samuwa.

Jagoran Bincike: Dr Yanling Liao, mataimakin farfesa a fannin ilimin yara.

Dokta Yanling Liao ta samu digirin digirgir a fannin ilmin halitta a jami'ar Xiamen, PR China, sannan ta samu digirin digirgir daga Sashen nazarin halittu a Kwalejin likitanci na Albert Einstein, New York, inda ta yi bincike kan tsarin sarrafa rubutun RNA. Ta yi karatun digiri na biyu a dakin gwaje-gwaje na Dr. Helen Blau a Sashen Nazarin Immunology & Microbiology a Makarantar Magunguna ta Jami'ar Stanford, California, sannan ta shiga dakin gwaje-gwajen Dr. Mitchell Cairo a Sashen Kula da Lafiyar Yara, Cibiyar Kiwon Lafiya ta Jami'ar Columbia, New York. Dokta Liao ta zama mataimakiyar Farfesa a fannin ilimin yara a shekara ta 2011 kuma mataimakiyar farfesa a fannin ilimin yara a shekarar 2014 a Kwalejin Kiwon Lafiya ta New York, inda babban bincikenta ya mayar da hankali kan ci gaba da haɓakar ƙwayoyin ƙwayoyin cuta da furotin don RDEB.

Mai binciken haɗin gwiwa: Farfesa Mitchell Cairo, Mataimakin Shugaban Sashen Harkokin Ilimin Yara & Farfesa na Pediatrics, Medicine, Pathology, Microbiology, Immunology, Cell Biology & Anatomy a NYMC.

Farfesa Mitchell Cairo a halin yanzu shine Mataimakin Shugaban kuma Farfesa (tare da aiki) a Sashen Kula da Yara a Kwalejin Kiwon Lafiya ta New York (NYMC). Ƙarin matsayinsa na jagoranci na yanzu sun haɗa da kasancewa Babban Jami'in Sashen Harkokin Ilimin Jiki na Yara, Oncology da Stem Cell Transplantation, Daraktan Shirye-shiryen na Adult & Pediatric BMT, Daraktan Cibiyar Ciwon daji da Matasa da Ciwon Jini, Likita da Daraktan Kimiyya na Cibiyar. GMP Cellular and Tissue Engineering Laboratory at Westchester Medical Center (WMC), Daraktan Kiwon Lafiya na WMC Shirin Hematotherapy da Shugaba na WMC Adult and Pediatric Cancer Program. Dokta Alkahira ƙarin alƙawura na ilimi sun haɗa da kasancewa Farfesa na Magunguna, Pathology, Microbiology and Immunology and Cell Biology and Anatomy and Public Health a NYMC.

"An gane da kyau cewa ƙumburi na yau da kullum da fibrosis suna taimakawa wajen bunkasa ciwon daji na squamous cell carcinoma a marasa lafiya tare da RDEB. Amsa mai kumburi, wanda shine tsarin tsaro na halitta a cikin jikinmu, yakamata a warware shi bayan kare kamuwa da cuta da / ko rauni, duk da haka ba a warware shi ba a cikin marasa lafiya tare da RDEB. Madadin haka, yana canzawa zuwa yanayin da ba a so a cikin waɗannan marasa lafiya. Don haka, bincikenmu zai taimaka mana gano yadda ƙwayoyin rigakafi a cikin fata ke canzawa tare da lokaci don amsa canje-canje a cikin microenvironment na dermal. Wannan binciken zai taimaka mana mu fahimci tsarin ƙumburi na yau da kullum da kuma gano maƙasudin sabon labari don magani ko rigakafin cututtuka na kullum da fibrosis a cikin marasa lafiya tare da RDEB."

Dr Yanling Liao

Taken Grant: Gano ingantattun ingantattun hanyoyin rigakafi masu alaƙa da fibrosis a cikin nau'ikan dabbobi na RDEB

Akwai nau'o'in kumburi iri biyu, na farko yana da matsakaicin ƙananan ƙwayoyin cuta (misali kasancewar kwayoyin cuta), ɗayan kuma idan babu ƙananan ƙwayoyin cuta, wanda ake kira bakararre kumburi. Siffar ma'anar ƙumburi bakararre ita ce sau da yawa yana iya haifar da tsari mai kumburi da fibrosis. Bisa ga binciken mu na farko na farko, yana yiwuwa a haifi marasa lafiya tare da RDEB tare da ƙumburi maras kyau kuma su kara dame su ta hanyar ƙananan ƙwayoyin cuta saboda rashin Collagen 7. Wannan ya kawo tambaya game da kalubale na tsarin da ke hade da EB - fiye da haka. fiye da kawai matsala tare da fata da mucosa. Ci gaba da ƙumburi da ba a warware ba sannan yana haifar da matsala na yau da kullum, fibrosis kuma a ƙarshe na iya danganta da ci gaban ciwon daji na squamous cell. Don haka yana da mahimmanci a fahimci hanyoyin wannan tsari na kumburin farko. Binciken da aka gabatar zai ƙunshi samfurin RDEB wanda ba shi da COL7A1 don bincika irin nau'in ƙwayoyin rigakafi da ke shiga cikin fata a ƙarƙashin yanayi mara kyau.

Ƙungiyar za ta kuma duba abin da siginar kwayoyin ke haifar da kutsawar su, yadda suke hulɗa da juna da kuma microenvironment na fata. Bisa ga waɗannan sakamakon, za su bincika idan za a iya dakatar da siginar kwayoyin halitta ko rage jinkirin ci gaba da ci gaban kumburi da fibrosis.
Abubuwan da ke cikin nau'ikan nau'ikan amsawar rigakafi guda biyu (na asali da daidaitawa), an nuna su duka don taka muhimmiyar rawa wajen haifar da fibrosis a cikin tsarin gabobin da yawa kamar huhu da hanta. Koyaya, rawar da suke takawa a cikin kumburi na yau da kullun da fibrosis a cikin RDEB ba a fahimta sosai ba.
Nazarin da aka tsara za su bincika jerin martanin rigakafi da alaƙar su tare da siginar sigina a cikin fata don fahimtar ci gaba da canji na amsawar rigakafi.
Ana fatan cewa ta hanyar ƙayyade hanyoyin siginar, wannan aikin zai bayyana hanyoyin da ke da alaƙa da kumburi da fibrosis, gano maƙasudin maƙasudin da za a yi don fara shiga tsakani da ci gaban labari da kuma ingantaccen maganin rigakafi a cikin RDEB.

Kumburi shine tsarin kariya na halitta na jiki daga kamuwa da cuta da/ko rauni. Duk da haka, yawancin bincike sun nuna cewa ciwon daji na squamous cell carcinomas a cikin marasa lafiya tare da RDEB sun taso a wuraren da ake ci gaba da kumburi. Fatar marasa lafiya tare da RDEB suna hade da raunuka da suka haifar da rauni da kuma ƙananan ƙwayoyin cuta. Yadda martanin kumburi ya samo asali zuwa yanayin da ba a so a cikin marasa lafiya tare da RDEB ba a bayyana a sarari ba. A cikin wannan binciken, mun gano cewa, ko da kafin ciwace-ciwacen daji ya faru, ƙwayoyin dermal sun riga sun nuna siffofin da ke tallafawa ci gaban ƙwayar cuta da kuma metastasis, kamar waɗanda aka gani a cikin fata mai girma. Waɗannan fasalulluka sun haɗa da canza amfani da makamashi (Anaerobic metabolism), ƙwayoyin epidermal masu yaduwa, haɓakar haɓakar ƙwayoyin cuta da kunnawa, kunna fibroblast, ingantaccen angiogenesis da dai sauransu. Bayananmu sun nuna cewa an kafa wannan ƙwayar cuta mai goyan bayan RDEB dermal niche (microenvironment dermal) kafin farawa. Canjin ƙwayar cuta kuma yana ba da shawarar cewa sa baki da wuri don daidaita wannan microenvironment na dermal ana buƙatar ga mutanen da ke da RDEB, don yiwuwar jinkirta ko hana ci gaban ƙari.

Mun kuma auna ma'auni daban-daban na kumburi a cikin fata kuma mun gano interleukin 1 (IL-1a) a matsayin babban mahimmanci (cytokine) wanda ya fara mayar da martani mai kumburi daga haihuwa kuma ya ci gaba da ci gaba da kumburi na kullum tare da wasu cytokines masu kumburi (irin su IL-6 da TNF). Mun kuma tabbatar da tasirin IL-1a akan gyaggyarawa phenotypes na RDEB fibroblasts. Nazarin mu ya nuna cewa hanawa na IL-1a, ko a hade tare da masu hanawa a kan wasu cytokines da suka bayyana a wani lokaci mai tsawo fiye da IL-1a, na iya zama tasiri mai mahimmanci na maganin kumburi. The an buga binciken wannan bincike akan layi.

Bincikenmu yana mai da hankali kan fahimtar tsarin kumburi a cikin ƙirar linzamin kwamfuta na RDEB. Mun yi nazarin kwayoyin halittar da aka bayyana a cikin nau'ikan tantanin halitta (kamar ƙwayoyin epidermal, ƙwayoyin dermal, ƙwayoyin rigakafi, ƙwayoyin jijiya da ƙwayoyin jini a cikin fata) a cikin mice na RDEB kuma idan aka kwatanta su da mice masu lafiya. Mun gano cewa duk sel sun sami canji na rayuwa zuwa ga glycolysis na aerobic, don mayar da martani ga yanayin dermal hypoxia (ƙananan oxygen). Ingantaccen glycolysis shine fitaccen siffa na ƙwayoyin cutar kansa da manufa don maganin ciwon daji. Mun gabatar da cewa siginar hypoxia da aka haifar da glycolysis na iya zama makasudin sa baki a cikin RDEB. Mun kuma sami wasu ƙayyadaddun maganganun kwayoyin halitta ko yawan tantanin halitta a cikin RDEB waɗanda ke da alaƙa da haɓakar cututtukan cututtuka na RDEB. Dangane da ƙara yawan maganganu na abubuwa da yawa waɗanda ke cikin madauki mara kyau, zamu iya yin hoton cewa fatar RDEB tana ƙoƙarin rama lalacewar nama ta hanyar ƙirƙirar yanayi mai hana rigakafi don haɓaka warkar da rauni.

Duk da haka, wannan yana cikin farashin rage yawan aikin kwayar cutar T (kamar yadda aka nuna ta hanyar ƙara yawan maganganun PD-1 akan ƙwayoyin T, wanda shine ma'auni don ƙaurawar ƙwayar cuta) da kuma ƙara haɗarin ci gaban ciwon daji. A gefe guda, wannan yana buɗe zaɓi don toshewar PD-1 don sake ƙarfafa aikin tantanin halitta T a cikin RDEB. Hakanan an kunna hanyoyin sigina daban-daban don mayar da martani ga kumburi. Muna ƙoƙarin gano abubuwan da ke daidaita kowace hanya kuma a wane lokaci abubuwan da suka bayyana da/ko suka ɓace. Wannan zai ba mu maƙasudai don shiga tsakani na warkewa. Ya zuwa yanzu, daya daga cikin abubuwan da aka ba da tabbacin da za su iya zama maƙasudin warkewa shine interleukin (IL) -1a, wanda matakinsa ya fi girma fiye da duk sauran abubuwan kumburi a jarirai kuma ya ci gaba da karuwa tare da shekaru. Wataƙila siginar haɗari ne a cikin RDEB da wuri wanda ke kunna duk ɓoyayyen ɓoyayyen ɓoyayyen ɓoyayyiyar kumburi. Sauran siginar haɗari na iya zama abin da ake kira cikakken 3 (C3). An gano wannan abu a cikin ruwan blister na jaririn RDEB na jariri kuma an bayyana shi sosai a cikin wani nau'i na fibroblast (kwayoyin dermal) waɗanda ke raba irin wannan kaddarorin kamar abin da za a iya samu a cikin fibroblasts masu ciwon daji.

Nazarin mu na gaba zai ƙayyade tasirin toshe IL1a da C3 akan hana kumburi a cikin RDEB. (Daga rahoton ci gaba na 2022.)