2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656720摘要：題目：局部缺血引發膀胱功能失調之機轉與預防及治療效應評估前言：越來越多的證據顯示缺血可能是部分病人（粥狀動脈硬化、老化、膀胱出口阻塞等）膀胱功能失調的原因。之前的動物實驗已經證實缺血會造成膀胱結構上的變化（平滑肌細胞死亡、去神經化、纖維化）及功能上的變化（膀胱過動、收縮力下降、彈性不佳）；然而，在分子生物學的角度，缺血性膀胱功能失調的機轉則需要進一步的研究。當細胞承受外界環境的壓力時，可能造成所謂的內質網壓力，並進一步引發細胞凋亡或細胞自噬；這樣的機轉已經在很多其他器官的缺血性病變中被發現，而我們認為這很可能也是缺血造成膀胱破壞及功能失調的機轉。假說：我們認為由缺血所造成的氧化壓力，會藉由內質網壓力、細胞凋亡、細胞自噬造成膀胱的破壞；而一些抗氧化劑的使用，可以改善因缺血所造成的膀胱破壞。材料和方法：這個計畫共分三個階段（年）第一階段：建立局部缺血鼠造成膀胱病變的動物模式，並初步探索各項可能造成疾病的致病機轉。第二階段：以第一階段的結果為基礎，進行各項分子生物學的研究。第三階段：探討綠茶、五淋散、印度鵝苺是否能改善缺血性膀胱病變。初步結果：我們初步的研究結果已經顯示將兩側老鼠膀胱動脈結紮二週至四週之後，能產生膀胱過動的現象，尿液及膀胱活體自由基上升（附件一）。這些結果已經初步符合我們的假設，值得進一步的研究。重要性：藉由這個計畫，我們可以更進一步的了解缺血性膀胱功能失調的機轉，並試驗抗氧化劑預防缺血性膀胱的效果。這些結果，將來經由更多的研究，也許能應用在臨床上治療因缺血所造成的下尿路症狀。<br> Abstract: Title: Therapeutic Mechanism and Medical Application of Ischemia Induced Bladder DysfunctionIntroduction: A growing body of evidence shows that ischemia may be the etiology of bladder dysfunction in patients with risk of bladder ischemia, such as aging, artherosclerosis, or bladder outlet obstruction. Previous studies showed that ischemia may lead to structural changes (loss of smooth muscle cells, denervation, and fibrosis) and functional changes (detrusor overactivity, impaired bladder contractility, and non-compliant) of urinary bladder in animal models. However, in the perspectives of molecular cell biology, the mechanism of ischemia-induced bladder dysfunction remains not fully understood. Under stress conditions, such as ischemia and oxidative stress, cells may suffer from endoplasmic reticulum (ER) stress, which may further lead to apoptosis or autophagy. The interplay between ER stress, apoptosis, and autophagy has been found in ischemia-related cellular damage in many organs, and we believe that it is also involved in the mechanism by which ischemia and oxidative stress cause bladder injury and dysfunction.Hypothesis: We hypothesize that the ischemia-induced oxidative stress causes bladder damage via mechanisms involving endoplasmic reticulum stress, autophagy, and apoptosis; the application of some antioxidants can attenuate the ischemic injury of urinary bladder.Material and Methods: The study comprises three stagesIn the first stage (year), we will establish the animal models of ischemic bladder, and collect the physiologic, histopathologic, and functional changes of urinary bladder following ischemia.In the second stage (year), we will focus on the pathophysiology of ischemic bladder dysfunction in the perspectives of molecular cell biology.In the third stage (year), we will investigate whether the application of green tea, Wu-Lin-San, or Amla can prevent ischemic bladder injury and dysfunction.Initial Results: Our preliminary experiment showed that ischemia achieved by ligating bilateral vesical arteries for 2 to 4 weeks was able to induce detrusor overactivity. Meanwhile, the urinary and bladder levels of reactive oxygen species significantly increased. The initial results support our hypothesis and potentiate our further research plan.Significance: Through this research, we will further understand the mechanism by ischemia causes bladder dysfunction and the effect of some antioxidant on prevention of ischemia-induced bladder dysfunction. The results may be valuable and can be applied clinically to treat ischemia-related lower urinary tract symptoms, although further studies are still required.缺血氧化壓力自由基活性氧化物質內質網壓力細胞凋亡細胞自噬老鼠膀胱膀胱過動症Ischemiaoxidative stressreactive oxygen speciesendoplasmic reticulum stressapoptosisautophagyratoveractive bladderdetrusor overactivity