2017-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643809摘要：由於成體哺乳類⼼肌細胞與存留之⼼臟前驅細胞的增⽣修補能⼒有限，以致於急性缺⾎傷害後取代損傷組織的能⼒不夠。 因此，科學上與臨床上急待突破能尋找到具刺激⼈類⼼臟再⽣能⼒並產⽣⼼臟保護作⽤的藥理標的。我們先前的研究發現A83-01(⼀個TGFβRI 抑制劑)能增加⼼臟前驅細胞表達survivin 來擴增⼼臟前驅細胞數量，並且活化⼼臟前驅細胞媒介的旁泌作⽤來增進⼼肌存活，藉此雙重作⽤顯著地改善受傷後⼼臟功能失常。A83-01 能促進⼼臟前驅細胞分泌較多的外吐⼩體；然⽽，其機制及內涵於外吐⼩體之⼼臟保護物質仍有待進⼀步研究釐清。因此，本研究計畫旨在：（1）第⼀年、全⾯性地定性⼼臟細胞及前驅細胞分泌之外吐⼩體對受傷後⼼臟重塑﹑⼼肌再⽣及⾻髓間質幹細胞移⾏到受傷⼼臟的功能⾓⾊與機制，（2）第⼆年、研究A83-01 是經由smad 依賴或⾮依賴途徑增加⼼臟前驅細胞外吐⼩體分泌，並瞭解增加分泌的外吐⼩體，在有或無A83-01 治療之受傷⼼臟，其功能及蛋⽩與微⼩核醣核酸表現型有否改變，（3）第三年、將評估化學結構最佳化之新穎ALK5 抑制劑於增加⼼臟前驅細胞分泌⼼臟保護外吐⼩體以促進⼼肌梗塞後⼼臟功能恢復的活體藥效，並建⽴⾎清中外吐⼩體之蛋⽩與微⼩核醣核酸表現型與⼼臟復原或⼼衰竭癒後的關係。本計畫預期能找出新穎的⼼臟保護藥物，以利未來進⼀步轉譯研究。<br> Abstract: Adult mammalian cardiomyocytes and resident cardiac progenitors have limitedproliferative capacity with poor ability to replace lost tissue after acute ischemic injury. Ascientific and clinical imperative breakthrough is to find the pharmacological targets thatcan stimulate regenerative capacity and exert cardioprotective action in human hearts. Ourprevious study found A83-01 (a TGFβRI blocker) treatment could prominently amelioratecardiac dysfunction in post-injured hearts through the stimulation of survivin autocrine incardiac progenitor cell (CPC) to increase its proliferation as well as the enhancement ofcardiomyocytes survival via paracrine. Furthermore, A83-01 could also prominently increaseexosomes secretion from CPC. However, it remains further investigation to clarify theunderlying mechanism and identify the cardioprotective mediators in the exosomes secretedfrom CPC and other cardiac cells. The objectives of the present project are (1) tocomprehensively characterize the functional role of cardiac cells- and CPC-secretedexosomes in the proximal cardiac remodeling, regeneration and the homing of distal bonemarrow mesenchymal stem cells to post-injured hearts as well as the underlying mechanismsin the first-year project, (2) to investigate whether a smad-dependent or -independentpathway mediated A83-01-stimulated exosome production in CPC as well as the alteredfunctioning and protein/miRNA profiling of the exosomes secreted from CPC in post-injuredheart treated with or without A83-01 in the second-year project, and (3) to assess thechemically optimized novel ALK5 inhibitors in the enhancement of cardioprotective exosome production to facilitate cardiac repair in post-myocardial infarct mice in vivo as well as toestablish the relationship of the protein/miRNA profiling in serum exosomes and cardiacrecovery or the prognosis of heart failure in the third-year project. It is expected this projectwill develop a novel class of cardioprotective drug to preserve myocardium for the futuretranslational research.