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  本文選題：帕金森病　切入點：交感神經(jīng)　出處：《首都醫(yī)科大學》2017年碩士論文　論文類型：學位論文

【摘要】：目的:以中樞黑質(zhì)中多巴胺能神經(jīng)元缺失為主要病理特征的帕金森病(Parkinson's disease,PD)的患病率和發(fā)病率逐年上升,已成為嚴重影響人類健康的重要疾病之一。其臨床主要表現(xiàn)為運動系統(tǒng)癥狀和非運動系統(tǒng)癥狀,而體重減輕是其非運動系統(tǒng)癥狀之一。探索影響PD病人體重減輕、脂肪減少的因素,是提高PD病人生活質(zhì)量的關鍵。棕色脂肪組織(BAT)作為一個特殊的脂肪組織,與骨骼肌同源,通過介導線粒體氧化呼吸鏈的解偶聯(lián)作用,消耗甘油三酯和自由脂肪酸參與脂質(zhì)代謝,是機體非震顫性產(chǎn)熱的主要來源。前期研究中,我們發(fā)現(xiàn)PD模型大鼠棕色脂肪組織的交感神經(jīng)活性增強,提示BAT可能與PD病人的脂肪減少、體重減輕具有相關性。設計和方法:分別將6-OHDA和生理鹽水注射到大鼠左側(cè)前腦內(nèi)側(cè)束制作PD模型和假手術(shù)(sham)大鼠,并同時切斷其中的25只PD模型大鼠和10只sham大鼠的棕色脂肪組織周圍的交感神經(jīng),從而抑制棕色脂肪組織的活性。9周后分別將另外25只PD模型大鼠和10只sham大鼠置于4℃冰箱中,每天檢測并記錄體溫。10周后,將四組大鼠麻醉、處死、并分別取出腎周、皮下、附睪和棕色脂肪組織并稱重。檢測棕色脂肪組織的交感神經(jīng)活性標記物-酪氨酸羥化酶、功能活性標記物UCP1、β3R的表達。檢測腎周、附睪、皮下脂肪組織中甘油三酯、自由脂肪酸和脂肪分解相關分子表達情況。結(jié)果:1.支配大鼠BAT的交感神經(jīng)活性及BAT功能相關分子的檢測酪氨酸羥化酶是經(jīng)典的交感神經(jīng)末梢活性標記物,通過Western blot實驗發(fā)現(xiàn),PD模型大鼠BAT的(Tyrosine hydroxylase)TH表達含量明顯高于sham組,功能標記物(uncoupling protein 1)UCP1、分解因子(β3-adrenergic receptor)β3R的含量也明顯增加。將模型置于4℃條件下9天,體溫檢測結(jié)果顯示,PD組大鼠的體溫恢復速度明顯較sham組快。2.去神經(jīng)大鼠BAT功能活性和體重的檢測去神經(jīng)組中BAT的TH和UCP1的表達水平明顯較非去神經(jīng)組降低,且具有統(tǒng)計學差異。RNA水平檢測顯示,去神經(jīng)組BAT中β3R的表達也明顯下降。由此說明,我們的去神經(jīng)手術(shù)是成功的,顯著降低了BAT的活性和功能。且去神經(jīng)組比非去神經(jīng)組的體重明顯增高,在腎周脂肪組織和附睪脂肪組織中也呈現(xiàn)相同的趨勢。3.各脂肪組織脂質(zhì)分解相關因子的檢測我們利用Elisa檢測各WATs和BAT中的甘油三酯(triglyceride,TG)和自由脂肪酸(nonesterified fatty acid,NEFA)的含量,結(jié)果顯示,與非去神經(jīng)組相比,在去神經(jīng)組的腎周脂肪組織(retroperitoneal WAT,r WAT)和附睪脂肪組織(epididymal WAT,e WAT)中,TG的含量升高,NEFA的含量降低。在s WAT和BAT中的變化不明顯。Elisa分別檢測r WAT、e WAT、s WAT的脂解相關酶PKA/P-HSL/MAGL/ATGL的水平,結(jié)果顯示,在r WAT和e WAT中上述5種脂解酶的含量在去神經(jīng)組中明顯降低,與β3R的表達呈一致性。而s WAT中變化不明顯。結(jié)論:黑質(zhì)紋狀體通路多巴胺能神經(jīng)元的損毀,降低了對支配棕色脂肪組織交感神經(jīng)高級中樞核團的抑制,間接地促進了支配棕色脂肪組織交感神經(jīng)活性的增加,使BAT產(chǎn)熱功能增強,對NEFA的利用率增加,從而促進了白色脂肪組織的分解,導致PD大鼠脂肪組織的減少和體重的減輕。
[Abstract]:Objective: to dopamine in the substantia nigra neurons lack the main pathological features of Parkinson's disease (Parkinson's, disease, PD) the prevalence and incidence increased year by year, has become one of the important diseases seriously affect human health. Its main clinical manifestations and symptoms of motion system of the non motor symptoms, and weight loss is the the non motor symptoms of PD patients. To explore the influence factors of weight loss, reduced fat, is the key to improve the quality of life of PD patients. Brown adipose tissue (BAT) as a special adipose tissue, and skeletal muscle of the same source, guide the uncoupling effect of mitochondrial respiratory chain mediated by the consumption of triglycerides and free fatty acids involved in lipid metabolism, the body is the main source of non tremor thermogenesis. In previous study, we found that enhanced sympathetic activity in brown adipose tissue of PD rats, suggesting that BAT may be with PD patients of fat reduction, weight loss is associated. Design and methods: 6-OHDA and saline was injected into the rat left medial forebrain bundle PD model (sham) and sham operation rats, and turn off the sympathetic nerve around one of the 25 PD rats and 10 sham rats, brown fat tissue, thus inhibiting the activity of brown adipose tissue after.9 weeks respectively in 25 PD rats and 10 sham rats at 4 C in the refrigerator, to detect and record the temperature every day after.10 weeks, four groups of rats were sacrificed, and anesthesia, respectively removed perirenal, epididymal and subcutaneous fat, brown tissue and weighed. Tyrosine hydroxylase activity of sympathetic nerve marker detection of brown adipose tissue, functional activity markers UCP1, 3R expression. The detection of perirenal, epididymal and subcutaneous adipose tissue triglyceride, feeling the freedom of expression of fatty acid and fat decomposition related molecules Results: 1. cases. Control of tyrosine hydroxylase activity and BAT molecular detection of sympathetic nerve function in BAT rats is sympathetic nerve activity markers classic, through Western blot experiments showed that the rat model of PD BAT (Tyrosine hydroxylase) TH expression was significantly higher than that of sham group, functional marker (uncoupling protein 1) UCP1 the decomposition factor (beta 3-adrenergic, receptor) levels of beta 3R also increased significantly. The model was placed in the temperature of 4 DEG C for 9 days, the temperature test results showed that the expression level of the rats in group PD the recovery rate of group sham was significantly higher than.2. to detect BAT activity and neural function of rats weight denervation group in BAT TH and UCP1 was significantly higher than the non denervated group decreased, and has showed significant difference in the.RNA level, the expression of 3R beta to nerve group BAT also decreased significantly. Therefore, our denervation surgery was successful, significant Reduce the activity and function of BAT. And the denervation group than in the non denervated group weight increased significantly, detected in perirenal adipose tissue and epididymal adipose tissue also showed the same trend.3. adipose tissue lipolysis related factors we use Elisa to detect the WATs and BAT in Gansu oil ester (triglyceride, TG three free fatty acid (nonesterified) and fatty acid, NEFA) display the results of the content, and non denervation group than in perirenal adipose tissue denervation group (retroperitoneal WAT, R WAT) and epididymal adipose tissue (epididymal WAT, e WAT), the content of TG increased, the content of NEFA was decreased. Changes in s WAT and BAT.Elisa were not obvious in detection of R WAT, e WAT, PKA/P-HSL/MAGL/ATGL s WAT the lipolytic enzyme level, results showed that in R WAT and E WAT in the content of the 5 kinds of lipolytic enzymes in to significantly lower nerve group, and 3R expression was Consistency. S WAT did not change significantly. Conclusion: nigrostriatal dopaminergic neuron damage reduced the inhibitory innervation of brown adipose tissue sympathetic senior central nuclei, indirectly promoting the increase of sympathetic activity of brown adipose tissue, increased BAT heat production rate increased to NEFA function. Use to promote the decomposition of white adipose tissue, lead to lessening the fat tissue of PD rats and weight.

【學位授予單位】：首都醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R742.5

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