Fragmented early life environmental and emotional / cognitive vulnerabilities

描述（由申请人提供）：这是一份针对青少年易患精神疾病的复杂发展机制的Conte中心的修订申请。这些通常被认为是在敏感的发育时期由遗传和环境影响的相互作用引起的，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还存在重大差距。指导这一修订应用的创新统一假设是，生命早期母体信号的紊乱模式，特别是它们的碎片化和不可预测性，在很大程度上导致了青少年的情感和认知脆弱性。在原审稿人建设性建议的指导下，强有力的初步数据现在支持这一假设。拟议中心的总体目标是执行一个多维和综合计划，将这一极其重要的临床问题带入动物和人类研究实验室。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，该中心旨在将结果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，一个大型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

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.