本文選題：血管性抑郁 + 蛋白質(zhì)組學�。� 參考：《第二軍醫(yī)大學》2017年碩士論文

【摘要】：目前,抑郁癥已成為全球最主要的精神衛(wèi)生問題,給社會帶來了沉重的負擔。血管性抑郁是抑郁癥的一種典型的亞型,主要由血管性疾病或腦血管危險因素引起,患者的表現(xiàn)除了情緒異常低落、失眠多夢、食欲不振等典型的抑郁樣消極癥狀外,還表現(xiàn)為行動功能障礙、精神運動性阻礙、思維緩慢,領(lǐng)悟能力也會明顯減弱,嚴重的還會導致自殺。近年來血管性抑郁在重癥抑郁癥患者中所占比重顯著升高,不僅嚴重影響患者的生活質(zhì)量,對患者的工作、家庭及社會都影響重大。但其現(xiàn)狀并不樂觀,由于其功能障礙嚴重、成因復雜,臨床診斷指標模糊,目前對于血管性抑郁的病理機制尚未有全面的闡釋,基礎(chǔ)性研究較為薄弱。因此血管性抑郁的治療效果也不理想、療程長且容易復發(fā)。為了積累對血管性抑郁的基礎(chǔ)性探索,為其機制的研究、臨床診斷標志物的發(fā)現(xiàn)以及治療藥物的開發(fā)做出一定的貢獻,本研究將基于液相-質(zhì)譜平臺的蛋白質(zhì)組學技術(shù)和代謝組學技術(shù)相結(jié)合,試圖建立針對血管性抑郁小鼠模型的蛋白代謝整體調(diào)控網(wǎng)絡(luò),較為全面的闡釋血管性抑郁對生物體的影響和擾動。為了達到上述目的,本研究采用雙側(cè)頸總動脈結(jié)扎的全腦缺血(GCI)方法來構(gòu)建血管性抑郁小鼠動物模型,通過對血管性抑郁小鼠海馬組織的代謝組學分析和iTRAQ標記的蛋白質(zhì)組學分析,我們共篩選得到了44個差異代謝物和304個差異蛋白質(zhì)。借助Ingenuity Pathway Analysis軟件我們對差異代謝物和蛋白質(zhì)進行了關(guān)聯(lián)及整合分析,構(gòu)建與血管性抑郁疾病相關(guān)聯(lián)的蛋白-代謝整體調(diào)控網(wǎng)絡(luò)。而后,我們使用LC-MS/MS,western blot和Rt-Q-PCR等技術(shù),對生物信息學分析聚焦通路所涉及的生物分子進行了定量驗證。驗證結(jié)果提示機體發(fā)生了神經(jīng)可塑性調(diào)節(jié)的改變、興奮性能神經(jīng)遞質(zhì)運輸及作用的變化、神經(jīng)細胞增殖與凋亡的失衡,以及氨基酸、脂質(zhì)及能量代謝的紊亂。在我們的組學分析中篩選到了這些受到擾動的通路中的蛋白質(zhì)及其下游代謝物。不同層次的生物分子間的關(guān)聯(lián),將為深入研究血管性抑郁的發(fā)生機制提供更有針對性以及可信度更高的著力方向。同時這些發(fā)生變化的生物分子也將成為血管性抑郁的潛在治療靶點或生物標志物。因此,本文呈現(xiàn)的這種將蛋白質(zhì)組學與代謝組學信息整合來準確快速地聚焦研究方向,篩選潛在靶點及生物標志物的方法和策略,對于像血管性抑郁這一類基礎(chǔ)研究尚未展開、積累較為薄弱的疾病對象來說,可以為更深層次的研究縮小范圍,提供更為精準,更為可信,更具開拓潛力的研究方向。同時,也有助于血管性抑郁疾病進一步的藥物發(fā)現(xiàn)和臨床診斷及治療手段的開發(fā),具有一定優(yōu)勢。
[Abstract]:At present, depression has become the most important mental health problem in the world, which brings a heavy burden to the society. Vascular depression is a typical subtype of depression, mainly caused by vascular diseases or cerebrovascular risk factors. It is also shown as movement dysfunction, psychomotor obstacle, slow thinking, obvious weakening of comprehension ability, and serious suicide. In recent years, the proportion of vascular depression in patients with severe depression has increased significantly, which not only seriously affects the quality of life of patients, but also has a significant impact on the work, family and society of patients. But its present situation is not optimistic, because its function obstacle is serious, the cause of formation is complex, the clinical diagnosis index is fuzzy, the pathological mechanism of vascular depression has not been fully explained at present, the basic research is relatively weak. Therefore, the treatment of vascular depression is not ideal, the course of treatment is long and easy to relapse. In order to accumulate the basic exploration of vascular depression, and to contribute to the study of its mechanism, the discovery of clinical diagnostic markers and the development of therapeutic drugs, In this study, proteomics and metabolic techniques based on liquid-mass spectrometry platform were combined to establish a global regulatory network of protein metabolism for vascular depression mice. A more comprehensive explanation of vascular depression on the biological impact and disturbance. In order to achieve the above purpose, the animal model of vascular depression in mice was established by global cerebral ischemia (GCI) with bilateral common carotid artery ligation. Through the metabolomics analysis of hippocampus and the proteomic analysis of iTRAQ labeling in the hippocampus of vascular depression mice, 44 differential metabolites and 304 differential proteins were screened out. With the help of Ingenuity Pathway Analysis software, the differential metabolites and proteins were analyzed and integrated to construct the protein-metabolism regulatory network associated with vascular depression. Then we used LC-MS / MS western blot and Rt-Q-PCR to quantitatively verify the biomolecules involved in the bioinformatics analysis of the focusing pathway. The results suggested that the changes of neuroplasticity regulation, the changes of neurotransmitter transport and action, the imbalance of nerve cell proliferation and apoptosis, and the disturbance of amino acid, lipid and energy metabolism. The proteins in these disturbed pathways and their downstream metabolites were screened in our cluster analysis. The relationship between biomolecules at different levels will provide a more specific and reliable direction for further study on the pathogenesis of vascular depression. These altered biomolecules will also be potential therapeutic targets or biomarkers for vascular depression. Therefore, the methods and strategies presented in this paper, which integrate proteomics and metabolomics information to accurately and quickly focus on the research direction, screen potential targets and biomarkers, have not been carried out for basic studies such as vascular depression. The accumulation of weak disease objects can narrow down the scope of deeper research and provide a more accurate, more reliable, more potential research direction. At the same time, it is helpful for the further discovery of drugs and the development of clinical diagnosis and treatment for vascular depression.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R749.4;R-332

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本文編號：1801588