2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660153摘要：自主神經病變是糖尿病的主要症狀包括無法排汗、姿勢性低血壓、腹瀉等。過去評估自主神經病變完全依賴功能檢查，功能性的檢查並無法釐清病變的病理所在 (localizationof the pathology) ，因此建立一套定量病理 (quantitative pathology) 與超微結構的研究系統，對於探討自主神經退化的機制有其需要性。我們將以兩種系統的神經退化來探討這些問題，即 (1)神經損傷：神經切斷 (nerve transaction) 和神經壓傷 (nerve crushing) 和(2) 糖尿病 (以streptozotoxin 誘導)。計畫之目標為：(1)建立一套可以定量的自主神經病變的病理系統，(2)探討血糖控制自主神經病變的影響，(3)探索可能的自主神經退化機制，並給予小分子來改變神經營養因子的表達 (expression of neurotrophins)，而達成促進神經再生的目的。首先，我們將建立一個以面積為基礎的定量系統 (area-based morphemetry)，以量化自主神經在標的組織之支配密度 (autonomic innervetion density)，特別是汗腺。這一量化系統並將以 stereology 為基礎之定量系統，加以驗證。第二個目標將以胰島素注射，來降低血糖，以探討血糖控制對自主神經病變之影響。在以stretozotoxin 誘發糖尿病後，部分糖尿病大鼠將給予胰島素，以瞭解自主神經病變的神經退化是否可逆，亦即是否可以減輕自主神經退化的病理變化與嚴重程度。神經營養因子的缺乏 (neurotrophin deficiency) 是糖尿病神經病變的重要機制，這一計畫將藉由給予小分子藥物 (4-methylcatechol) ，增加神經營養因子，來檢驗這一假說。預期這一計畫之研究成果，將可以對於糖尿病所致之自主神經病變的病理機制及治療提供新的方向。<br> Abstract: Autonomic neuropathies are major presentations of diabetes including sudomotor failure,orthostatic hypotension, and diarrhea. In the past, the assessments of autonomic neuropathiesdepended on functional examinations. There are several issues which hinder the studies ofautonomic neuropathy. These include: (1) pathologic demonstration of peripheral nervedegeneration, and (2) quantitation of pathological changes. In this proposal, we willinvestigate these issues in two systems of nerve degeneration, i.e. (1) nerve injury by nervetransection and by nerve crushing and (2) streptozotoxin-induced diabetes onSprague-Dawley rats. The aims are to (1) establish a system of quantitative pathology ofautonomic innervation of the target tissues, and (2) examine the effects of glycemic controlson autonomic innervation, and (3) explore potential mechanisms of autonomic nervedegeneration and reversing these changes by administration of small molecules to enhanceneurotrophin expression.Based on immunohistochemistry, we will first establish an area-based morphometricsystem to quantitate the autonomic innervation in the target tissues and organs, in particularthe sweat glands, and the cardiovascular and gastrointestinal systems. The results will bevalidated with a stereologic approach, an unbiased and systemic sampling. The results ofimmunohistochemistry will be correlated with ultrastructural studies which will showevidence of nerve degeneration at the target tissues.The second aim of this proposal will examine the effect of glycemic control onautonomic innervation. After stretozotoxin-induced diabetes, diabetic animals will be furtherdivided into two groups: (1) diabetes alone and (2) diabetes treated with insulin. Thequantitative nerve pathology of autonomic innervation of these two groups will be comparedwith the control group to understand whether autonomic neuropathy will be reversible bynormalization of glycemia.Given that (1) nerve degeneration frequently becomes permanent in diabetic patients and(2) neurotrophin deficiency is a major mechanism of diabetic neuropathy, this proposal willtest the hypothesis that small compound will enhance autonomic nerve regeneration byenhancing neurotrophin synthesis in both nerve injury and diabetes system.The results of this proposal will improve the quantitative assessments of autonomicneuropathy and the understanding of neurodegeneration and nerve regeneration in diabeticautonomic neuropathy.糖尿病神經病變糖化血色素自主神經病變心臟自主神經病變心跳變異率汗腺神經皮膚切片