2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658193摘要：膀胱出口阻塞 (bladder outlet obstruction; BOO)是常見的泌尿科疾病，與許多泌尿科的疾病有關。過去的研究顯示膀胱出口阻塞造成膀胱傷害的機轉是因為過度的膀胱張力會導致缺血（ischemia），而引發一連串的細胞傷害，最終將造成膀胱組織學型態及功能的變化。這種因為缺血造成細胞傷害的相關機轉包括氧化壓力(oxidative stress)、及氮化合物(nitrogen species; iNOS)、發炎反應 (inflammation)，及細胞死亡及保護機轉如內質網壓力（endoplasmic reticulum stress；ER stress）等。這些機轉在膀胱出口阻塞造成的膀胱功能變化所扮演的角色，仍亟待研究。此議題仍有許多值得探討之處：包括膀胱出口阻塞造成膀胱傷害的時序性變化仍然不明，而且目前臨床上仍無可用之藥物減輕膀胱傷害。我們設計此一研究，主要目的在探討在膀胱出口阻塞造成膀胱傷害之機轉，尤其是內質網壓力所扮演的角色。利用此細胞傷害或保護機轉，找尋新的治療藥物並發展新的治療模式。此為三年計畫第一年， 目標在建立膀胱出口阻塞造成膀胱傷害之動物模式，並探討造成膀胱出口阻塞造成膀胱傷害之機轉，我們將著重於內質網壓力作用所扮演之角色，同時釐清膀胱之傷害之時序性。第二年， 第二年，根據第一年研究發現之結果，尋找可能在急性期(<24hr)及亞急性期（24hr -3天）能減輕膀胱傷害的藥物，尤其是針對內質網壓力之機轉之調控藥物。吾人之初步結果發現EGCG對膀胱出口阻塞造成膀胱傷害有保護作用，其機制可能是透過抑制ER stress之作用機轉。此外，也將確認這些藥物之作用機轉，及與細胞凋亡的關係。第三年， 第三年評估藥物證實此藥物在慢性膀胱出口阻塞（28天及56 天）之治療效果，並利用活體測量其膀胱功能之改善情況，以證實此藥物之長期效果，並研究其最佳作用的給藥劑量、途徑。我們的初步結果顯示內質網壓力，發炎反應均與膀胱出口阻塞造成之膀胱傷害有關 (Preliminary data: Figure 3-6)，而EGCG (Epigallocatechin gallate)是一可能的藥物，能減輕膀胱傷害(Figure 7)。吾人相信，本研究將有助於了解膀胱出口阻塞之細胞傷害機轉，並藉此能找到有效之藥物，發展新的治療模式，日後能進一步應用於臨床。<br> Abstract: Bladder outlet obstruction (BOO) is a common outcomes of many urological disease. However, the underlying mechanism of BOO-induced bladder injury remains unclear. Several previous reports suggested that excessive distension of bladder caused ischemia and consequent hypoxia, which is implicated in structural and functional alterations of the urinary bladder. Tissue hypoxia has been reported to be associated with reactive oxygen species (ROS), nitrogen species, inflammation, endoplasmic reticulum (ER) stress. What is the role of these mechanisms play in the pathogenesis of BOO-induced bladder injury, especially ER stress remains unclear.In this project, we try to examine involvement of ER stress in the pathogenesis of BOO-induced bladder injury.We design the 3-year study.In the first year, we aim to establish experimental animal model of BOO and investigate the underlying mechanisms of BOO-induced bladder injury. We will focus on ER stress. Meanwhile, we try to clarify the temporal change of bladder injury after BOO. Our perliminaryIn the second year, we will apply the results we obtained in the first year and search for the possible drugs to alleviate BOO-induced bladder injury in acute phase (<24hr) and subacute stage (24hr – 3days). Besides, we will validate the therapeutic mechanisms of candidate drugs.In the third year, we aim to investigate the protective effect of the candidate drugs in chronic phase (7 days - 28 days) of BOO-induced bladder injury. We will not only evaluate the histologic change but also the detrusor function by in vivo cystometry and ex vivo organ bath method. Besides, we will test the different route (i.v., i.p., p.o.) and dosage of administering the candidate drug in vivo.Our preliminary data showed that the involvement of ER stress, inflammation and iNOS in the pathogenesis of BOO-induced apoptosis (Figure 3-6). EGCG (Epigallocatechin gallate) was a candidate compound to alleviate bladder injury (Figure 7). We are confident that we will obtain the promising results, which will have important implications for the development of novel therapeutic strategies to reverse bladder damage resulting from BOO.膀胱出口阻塞內質網壓力細胞凋亡膀胱壓力