脑源性神经营养因子、创伤后应激障碍、社会环境因素相互作用对糖脂代谢的影响及其分子机制研究

In this study, the traditional biomedical model will be substantially broken through, and the new bio-psycho-social medical model will be fully adopted. Subjects with or without posttraumatic stress disorder (PTSD) were enrolled from the disaster area of Wenchuan earthquake, which had produced a natural PTSD model of big sample size. Brain-derived neurotrophic factor (BDNF) will be selected as the molecular target of biological factor for this study. PTSD will be analyzed as a psychological factor. Diets, life style (smoking, acohol consumption, food preference, and exercises will be included), family income, education levels of the subjects and their parents, occupation, the knowledge of nutrition and health the subjects have will be analyzed as social factors. After a follow-up of 3 investigations, the BDNF genetic variations (Val66Met), secretion (measured as the total plasma level of proBDNF and BDNF) and maturation (measured as the plasma level of BDNF and the proBDNF/BDNF ratios); PTSD; and the social factors and their interactions will be analyzed in the subjects on the levels of weight, body mass index, waist circumference, hip circumference, the ratio of waist circumference to hip circumference, blood pressure, blood glucose, plasma triglycerides, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol. PTSD rats will be introduced. Psychological behaviors will be analyzed between the rats with and without PTSD, and the diagnositic criteria of PTSD will be established for rat. Thereafter, the pilot analyse will be made of the interaction between PTSD and diets on the rat levels of plasma glucose and lipids. To our knowledge, no studies have been reported before to integrate the effects of bio, psycho, and social factors on the metabolisms of glucose, cholesterol and triglycerides, which may provide new insight into the development and its molecular mechanisms of cardiovascular diseases.

心血管病研究重生物因素，轻社会心理，更忽视其相互影响的作用。我们近年发现遗传与环境因素相互作用影响血脂等，预试提示脑源性神经营养因子(BDNF)与心理应激及血脂有关。我们假设，BDNF系统与心理、社会因素相互作用，影响BDNF及受体基因表达的组织特异性、分泌及成熟,通过p75及TrkB信号系统影响糖脂代谢。我们将采用汶川大地震后心理障碍(创伤后应激障碍，PTSD)大样本，分析PTSD、社会环境因素、BDNF Val66Met、血浆proBDNF、BDNF及其比值的相互影响与BMI、腰臀比、血糖、血脂的关系；建立大鼠应激动物模式，分析建立PTSD大鼠模型的判断标准，初步分析PTSD与膳食的相互作用对大鼠血糖、血脂的影响。国内外未见报道，为心血管病防治提供新思路，可能产生新理论。

作为小额探索项目，本项目的目标调整为：围绕评审专家提出的问题，展开前期研究，为最终完成该项目做好知识、技术和人才方面的准备。.发现汶川地震志愿者中，多数仍然摄取传统高糖低脂膳食，摄取高糖低脂膳食男性收缩压和脉压差比摄取非高糖低脂膳食男性低。这可能是一些地方中国人冠心病发病率比其他人种或其它地区人低的原因之一。SCI论文发表在BioScience Trends 2014; 8(2):132-137。.抑郁与PTSD常常共患；adiponectin不仅调节代谢，也可能与抑郁有关，可能是本项目通过BDNF研究生物、心理、社会环境因素相互作用对糖脂代谢影响的重要靶点之一。首次证实adiponectin基因rs1501299位点T 等位基因与女性青少年抑郁康复中后期的发病率降低和病情缓解有关。论文已经被Journal of Affective Disorders（IF=3.705）接受，即将发表。.发现脂蛋白脂肪酶基因rs326多态性G等位基因与男性健康汉族青年高糖低脂膳食后血浆HDL-C 和Apo A-I水平升高相关联。SCI论文发表在International Journal of Environmental Research and Public Health 2014; 11:4544-4554。发现高糖低脂膳食诱导的血浆log(TG/HDL-C)升高和LDL-C/HDL-C降低与ABCA1基因R219K多态性的关联在健康中国汉族男女青少年中不相同。SCI论文发表在Biological Research 2014; 47:4。.首次发现雄性PTSD模型大鼠大脑皮质BDNF基因外显子IV特异位点甲基化水平与血proBDNF有关，血细胞DNA相应位点甲基化与血proBDNF水平无关，这种相关性没在雌性大鼠中发现。不仅为近年来关于外周血DNA甲基化能否反映大脑DNA甲基化的激烈争论提供了直接的证据和答案，还进一步证实，探讨DNA甲基化与表型的关系，应该更关注量的变化和位点特异性。完成的论文已经投往Biological Psychiatry（IF=9.472），正在接受审稿。.经教育部国际合作与交流司批准（教外司际[2014] 907号），于2014 年9 月11 日至13 日在四川大学主办了“四川大学-南昌大学-冈山县立大学-又松大学联合营养学术会”。