Epigenetics behind long-term and transgenerational effects of adolescent behavior

描述（由申请人提供）：正在提出的赠款“青少年行为的长期和跨代影响背后的机制”将解决挑战领域（15）转化科学和特定挑战主题15-AA-101* 确定青少年行为是否以及如何影响发育中大脑的连接。大量的人类和动物数据都支持这样一种观点，即青少年的行为会对个人产生终身影响。这种敏感性可能部分来自大脑功能的巨大发展变化，这些变化在这个时候发生，以产生独立的技能。使这一现象更加复杂的是，与毒品有关的冒险行为增加，使他们倾向于开始使用成瘾药物。此外，青春期的大脑可塑性也可能有助于提高对压力长期负面后果的敏感性。更戏剧性的是，新的研究表明，在青年时期因环境而获得的某些品质可能会传递给未来的后代，从而可能放大青少年消极（或积极）行为的后果。许多研究已经开始揭示青少年时期的负面（和正面）经历，例如青少年接触尼古丁或社会压力的不良影响，或丰富环境的积极影响，对终身健康和福祉有长期影响。然而，他们关注的是个体研究者感兴趣的特定生化途径和生理过程中涉及的基因产物。在大多数情况下，这些影响背后的分子机制尚未被揭示，阻止了严格的测试，以确定它们是否与这些特定的青少年行为引起的健康问题的长期脆弱性在生理上相关。因此，在这项由塔夫茨大学医学院的Feig实验室、哈佛大学的Meissner实验室和布罗德研究所共同努力的提案中，我们将进行无偏的全基因组筛选，以检测大脑适当区域中显示经验诱导的所有基因，DNA甲基化和/或组蛋白修饰的长期变化可能会对健康产生长期的负面或正面影响。此外，我们将调查这些青少年经历的任何表观遗传诱导效应是否会传递给下一代。预计通过确定特定“消极”和“积极”青少年行为的新的持久和/或跨代效应物，这项研究将产生新的假设，这些假设开始回答本挑战领域提出的问题，即青少年行为如何“重新连接”发育中的大脑，从而造成脆弱性的一些持续的健康问题，包括心理健康障碍.和上瘾。“这项研究还将提出表观遗传机制，通过这些机制调节这些效应物表达的长期和/或跨代变化。因此，它将建议策略，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终身（和/或跨代）健康和幸福方面的作用。 公共卫生相关性：虽然一个人的遗传蓝图对他/她对疾病的易感性有很大的贡献，但很明显，一个人所生活的环境会影响如何阅读蓝图。这一点在青少年时期尤为重要，因为有大量证据表明，青少年时期的一些经历，如接触尼古丁或社会压力，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，这些青少年行为可能会影响未来的后代，当他们是青少年。这项提案将利用最先进的工具来确定这些青少年的经历如何通过改变基因阅读方式的长期结构修饰产生影响。预计这些信息将产生新的假设，如何扭转不良青少年行为的长期后果。

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.