Fragmented early life environmental and emotional / cognitive vulnerabilities

描述(由申请人提供)：这是一份修订后的孔特中心申请，旨在解决导致青少年易患精神疾病的复杂发育机制。这些通常被认为是由敏感发育时期的遗传和环境影响相互作用引起的，然而，我们对这些信号的性质以及它们促进疾病的机制的了解存在重大差距。指导这一修订应用的创新统一假设是，生命早期母亲信号的干扰模式，特别是它们的碎片化和不可预测性，极大地促进了青少年的情感和认知脆弱性。在最初评价者的建设性建议的指导下，强劲的初步数据现在支持这一假设。拟建中心的首要目标是执行一项多维度的综合计划，将这一极其重要的临床问题带入动物和人类研究实验室。该中心利用它们的互补优势，采用跨物种平台和复杂的协调分析方法，旨在将由此产生的发现转化为具有临床意义的预测模型。该中心的方法受益于一个独特的资源，一个庞大的特征良好的人类队列，进行从胎儿生活到青春期的纵向和横断面研究。中心研究将集中于 在这个队列和相关动物模型中的高级结构和功能脑成像，结合最先进的分子方法在时间和空间上进行基因调控。中心的目标是(1)使用传统和创新的方法，表征影响跨物种青少年脆弱性的出生前和出生后母体信号的模式，并生成婴儿期、儿童期和青春期改变的行为的轨迹；(2)利用人类和啮齿动物的共同平台，包括结构和功能成像，以及啮齿动物的机制研究，解决潜在的潜在机制；3)通过强大的统计/计算方法，将行为和成像结果随时间结合起来，为预示病理的青少年行为生成潜在的预测模型。该中心的重要性来自于通过强大的、跨物种的多学科、最先进的方法解决关键的临床问题。该中心测试了一个高度创新的假说，该假说建立在大量现有的人类和实验文献的基础上，并提供了一个理论统一的框架。中心方法的主要资产包括庞大的纵向人类队列、预测性动物模型、跨物种的通用方法平台、强大的初步数据、改进的项目设计和数据流的整合，以及对相互依赖的大型数据集及其集成到预测模型中的严谨和创新分析。因此，该中心产生的信息的影响将是巨大的，旨在改变我们对早期生活环境如何导致影响20%青少年的障碍的理解。情绪问题影响着数以百万计的美国人，通常始于青春期。虽然我们知道早期生活事件可能会导致这些问题的出现，但我们对其机制知之甚少。一群拥有不同专业知识的科学家联合起来，利用动物模型和大脑扫描来揭示这些机制，询问母亲在出生前后发出的信号是否在造成情感和认知问题的脆弱性方面起到了重要作用。

DESCRIPTION (provided by applicant): This is a revised application for a Conte Center addressing the complex developmental mechanisms contributing to adolescent vulnerabilities to mental illnesses. These are generally believed to arise from an interaction of genetic and environmental influences during sensitive developmental epochs, yet there are major gaps in our knowledge regarding the nature of these signals, and the mechanisms by which they promote disease. The innovative unifying hypothesis guiding this revised application is that disturbed patterns of maternal signals early in life, especially their fragmentation and unpredictability, contribute greatly to adolescent emotional and cognitive vulnerabilities. Guided by constructive suggestions of the original Reviewers, strong preliminary data now support this hypothesis. The overarching goal of the proposed Center is to execute a multi-dimensional and integrated plan that brings this exceedingly important clinical problem into both animal and human research laboratories. Capitalizing on their complementary strengths and employing cross-species platforms and sophisticated coordinated analytical methods, the Center aims to translate the resulting discoveries into clinically significant predictive models. The Centers approach benefits from a unique resource, a large well-characterized human cohort, to perform longitudinal and cross-sectional studies from fetal life to adolescence. Center research will focus on advanced structural and functional brain imaging in this cohort and in cognate animal models, combined with state-of-the-art molecular approaches to gene regulation in time and space. Center Aims will (1) characterize patterns of pre- and postnatal maternal signals that influence adolescent vulnerabilities across species, using conventional and innovative methods, and generate trajectories of altered behaviors in infancy, childhood and adolescence; (2) address the potential underlying mechanisms using common platforms in human and rodents, including structural and functional imaging, and mechanistic studies in rodents; 3) through a strong Statistics / Computational approach, combine behavioral and imaging outcomes along time to generate potentially predictive models for adolescent behaviors that augur pathology. The Center's significance derives from addressing crucial clinical questions via robust, cross-species multidisciplinary, state-of-the-art approaches. The Center tests a highly innovative hypothesis that builds on and provides a theoretical unifying framework for a large existing human and experimental literature. Major assets of the Center approach include a large longitudinal human cohort, predictive animal models, common methodological platforms across species, strong preliminary data, improved integration of Projects' design and data flow and rigorous and innovative analyses of the large and interdependent data sets and their integration into predictive models. Thus, the impact of the information generated by the Center will be substantial, aiming to transform our understanding of how early life environment contributes to disorders that affect 20% of adolescents. Emotional problems affect millions of Americans, and often start in adolescence. While we know that early-life events might contribute to the emergence of these problems, we know little about the mechanisms. A group of Scientists with diverse expertise combine to ask if signals from the mother before and after birth are important in creating vulnerabilities to emotional and cognitive problems, using animal models and brain scans to uncover the mechanisms.