Epigenetics behind long-term and transgenerational effects of adolescent behavior

描述(由申请者提供)：拟议的“青少年行为长期和跨代影响背后的机制”将涉及挑战领域(15)转化科学，以及确定青少年行为是否以及如何影响发育中大脑中的连接的具体挑战主题15-AA-101*。大量的人类和动物数据都支持这样的观点，即青少年的行为可以对个人产生终生影响。这种敏感度可能部分来自于大脑功能的戏剧性发展变化，这些变化正在发生，以产生独立技能。使这一现象更加复杂的是，青少年相关的冒险行为增加，这使他们倾向于开始使用成瘾药物。此外，青春期大脑的可塑性也可能有助于提高对压力的长期负面后果的敏感性。更具戏剧性的是，新的研究表明，青年时期对环境做出反应而获得的某些品质可能会遗传给未来的后代，这可能会放大青少年消极(或积极)行为的后果。许多研究已经开始揭示青春期的消极(和积极)经历如何对青少年暴露在尼古丁或社会压力中的不良影响，或丰富环境的积极影响，对终身健康和福祉产生长期影响。然而，他们把重点放在涉及个别研究人员感兴趣的特定生化途径和生理过程的基因产品上。在大多数情况下，这些影响的分子机制尚未被揭示，这阻碍了对它们是否在生理上与因这些特定的青少年行为而发生的长期健康问题的脆弱性进行严格测试。因此，在这项由塔夫茨大学医学院的Feig实验室和哈佛大学的迈斯纳实验室以及布罗德研究所共同努力的提案中，我们将进行无偏见的全基因组筛选，以检测大脑适当区域中所有显示经验诱导的DNA甲基化和/或组蛋白修饰的长期变化的基因，这些变化可能会对健康产生长期的负面或积极影响。此外，我们将调查这些青春期经历的任何表观遗传诱导的影响是否会传递给下一代。预计通过识别特定的“消极”和“积极”青少年行为的新的长期和/或跨代影响因素，这项研究将产生新的假设，开始回答这个挑战领域中提出的问题，即青少年行为如何“重新连接(S)发育中的大脑，从而造成一些持续性健康问题的脆弱性，包括精神健康障碍……和成瘾。”这项研究还将提出表观遗传学机制，通过这些机制来调节这些效应器表达的长期和/或跨代变化。因此，它将提出策略，专门阻止他们对小鼠青春期行为的反应，以测试他们在“这一时期表现出的行为如何影响一生(和/或跨代)健康和福祉”中所扮演的角色。 公共卫生相关性：尽管一个人的基因蓝图极大地影响了他/她对疾病的易感性，但很明显，一个人所处的环境会影响对该蓝图的阅读方式。这一点在青春期尤其重要，因为大量证据表明，青春期的一些经历，如接触尼古丁或社交压力，会对终身健康和福祉产生负面影响。我们的新数据甚至表明，这些青春期的行为可能会影响未来的后代，当他们是青少年的时候。这项提议将利用最先进的工具来确定这些青少年的经历是如何通过改变阅读方式的长期基因结构修改来产生影响的。预计这些信息将为如何扭转不良青少年行为的长期后果产生新的假设。

DESCRIPTION (provided by applicant): The grant being proposed "Mechanisms behind long-term and transgenerational effects of adolescent behavior" will address the Challenge Area (15) Translational Science, and the Specific Challenge Topic 15-AA-101* Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. A large body of both human and animal data support the idea that adolescent behaviors can have life-long effects on an individual. This sensitivity may derive, in part, from the dramatic developmental changes in brain function that are taking place at this time to generate skills for independence. Compounding this phenomenon is the adolescent-associated increase in risk-taking that predisposes them to initiate the use of addictive drugs. In addition, brain plasticity during adolescence may also contribute to heightened sensitivity to the long-term negative consequences of stress. Even more dramatic are new studies demonstrating that certain qualities acquired during youth in response to their environment may be passed on to future offspring, potentially magnifying the consequences of negative (or positive) adolescent behaviors. Many studies have begun to reveal how negative (and positive) experiences during adolescence, such as the ill-effects on adolescent exposure to nicotine or social stress, or the positive effects of an enriched environment, have long-term effects on life-long health and well being. However, they have focused on gene products involved in particular biochemical pathways and physiological processes of interest to individual investigators. In most cases molecular mechanisms underlying these effects have not been revealed, preventing rigorous test of whether they are physiologically relevant to long-lasting vulnerability to health problems that occurs in response to these specific adolescent behaviors. Thus, in this proposal, which is a joint effort by the Feig lab at Tufts University School of Medicine and the Meissner Lab at Harvard University and the Broad Institute, we will perform unbiased genome-wide screens to detect all genes in appropriate regions of the brain that display experience-induced, long-term changes in DNA methylation and/or histone modification that could that could account for long-term negative or positive consequences on health. Moreover, we will investigate whether any epigenetic-induced effects of these adolescent experiences are transmitted to the next generation It is anticipated that by identifying new long-lasting and/or transgenerational effectors of specific "negative" and "positive" adolescent behaviors, this study will generate new hypotheses that begin to answer the question proposed in this Challenge Area of how adolescent behavior "rewire(s) the developing brain thereby creating vulnerability for a number of persistent health problems including mental health disorders.....and addiction." This study will also suggest epigenetic mechanisms by which long-term and/or transgenerational changes in the expression of these effectors are regulated. As such, it will suggest strategies to specifically block their response to adolescent behaviors in mice to test their role in how "behaviors exhibited during this period can influence lifetime (and/or transgenerational) health and well-being. PUBLIC HEALTH RELEVANCE: Although a person's genetic blueprint strongly contributes to his/her susceptibility to disease, it is clear that the environment in which one lives influences how that blueprint is read. This appears to be particularly important during adolescent years where substantial evidence implies that some experiences during adolescence, such as exposure to nicotine or social stress have negative consequences on life-long health and well being. Our new data even suggest that these adolescent behaviors may influence future offspring when they are adolescents. This proposal will take advantage of state of the art tools to identify how these adolescent experiences have their effect through long-term structural modifications of genes that changes the way they are read. It is anticipated that this information will generate new hypotheses for how to reverse the long-lasting consequences of poor adolescent behaviors.