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- 저자 : 샤히나아크터 (검색결과 1 건)
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프리온 분해 단백질 발견과 angiopoietin-like Proteinol 실험실 조건에서 조혈모세포 증식과 생존에 미치는 영향
샤히나아크터 전북대학교 의학전문대학원 2013 국내박사
Removal of misfolded prion (PrPSc) in brain and in vitro expansion of hematopoietic stem cells (HSCs) are the most and important challenges in biomedical sciences. During my PhD researches, I identified a serine protease that degraded specifically PrPSc, and studied in vitro HSCs expansion by angiopoietin-like proteins. Using the bipartite galactosidase-4-upstream activating sequence (GAL4-UAS) expression system, I generated transgenic Drosophila which pan-neuronally expressed wild-type (WT) mouse prion protein (mPrP) or the serine protease or co-expressed mPrP with the serine protease. Abnormal accumulation of PK-resistant PrPSc, reduced lifespan, locomotor dysfunction, and rough eyes were resulted in 40 to 60-day-old mPrP expressed Drosophila indicating a toxic dominant mechanism of PrP for the etiopathogenesis of prion diseases (PrD). By contrast, co-expression of the serine protease with PrP showed that the serine protease completely detoxified misfolded PrP-induced neurotoxicity by degrading PK-resistant misfolded PrP, thereby preserved the normal lifespan along with strong positive locomotion, and normal eye development. In vitro enzymatic assay also showed that the serine protease had proteolytic activity toward PK-resistant misfolded PrP and this proteolysis was inhibited by UCF-101, a serine protease specific inhibitor. However, transgenic flies expressing serine protease displayed no pathological or phenotypical abnormalities rather it showed increased lifespan along with strong negative geotactic response. Confocal microscopic studies showed that the serine protease clearly detoxified abnormally accumulated PrP in transgenic Drosophila and co-localizes with PrP in the endoplasmic reticulum (ER). In vivo analyses of mutated serine protease demonstrated that mutant serine protease failed to alleviate the abnormal accumulation of α-synuclein that causes not only PD but also plays a role in regulating abnormal accumulation of misfolded PrP. I studied the functional role of mouse Angptls 1, 2, 3, 4, 6, and 7 and growth factors SCF, TPO, IGF-2, and FGF-1 on purified mouse Sca-1+ HSCs. None of the Angptls stimulated HSCs proliferation, enhanced, or inhibited HSCs colony formation, but they did support the survival of HSCs. By contrast, any of the six Angptls together with saturating levels of growth factors dramatically stimulated a 3- to 4.5-fold net expansion of HSCs compared to stimulation with a combination of those growth factors alone leading to an understanding of the basic function of Angptls and growth factors on signaling pathways for the survival as well as expansion of HSCs. Altogether, the results I demonstrate here addressing that the identified serine protease acts to detoxify misfolded PrP to protect PrD and the beneficial effects of Angptls on HSCs survival and expansion.
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