Gene-Environment Interactions for Cortical Development and Schizophrenia

 描述(申请人提供)：精神分裂症(SZ)是一种衰弱的疾病，起病于青壮年，对个人和社会都有深远的影响。自2008年以来，我们在P20和P50支持机制下，为这一重要的医学问题做出了多学科的努力。基于我们已发表的工作、有希望的初步结果和完善的实验策略，我们现在概念化一种新的协作性、假设驱动的研究策略，以实现对SZ和相关条件的机械性理解。通过我们过去的研究，我们在五个主要领域取得了成果：(I)微管相关途径作为SZ青春期后病理生理学的发育驱动因素；(Ii)SZ患者应激相关分子的变化，尤其是在疾病的早期阶段；(Iii)青春期皮质异常成熟：关键时期潜在的基因-环境相互作用；(Iv)神经电路引导的与SZ相关的小鼠模型的行为特征；以及(V)RNA测序数据分析方面的技术进展。根据我们自己的初步数据以及其他小组发表的信息，我们计划在未来五年内解决以下假设：(A)SZ(或SZ的子集)的遗传风险会在大脑发育早期引发“轻度”缺陷；(B)这种缺陷会在青春期后期引发更显著的分子和电路相关变化；(C)青春期激活的应激相关分子会导致无症状、脆弱的大脑进入有症状的病理状态，直接影响兴奋性抑制(E-I)失衡；(D) 青春期的心理社会应激会进一步加剧过渡期；(E)干预压力相关的过渡期是SZ的关键治疗策略。为了验证这些假说，我们提出了以下三个目标：(1)确定编码微管相关蛋白的基因(微管基因)对SZ病理生理学的贡献，特别是对SZ的一个子集，其中神经发育的影响可能更强；(2)确定青春期后“微管”基因的遗传风险如何引发前额叶皮质(PFC)的变化，以及青少年社会应激如何加剧这种变化；以及(3)研究应激相关分子如何直接影响和损害导致青春期E-I失衡的神经底物，从而导致青春期认知功能障碍，以及青春期应激源如何加剧这些变化。为了解决这些问题，我们提出了3个项目和3个完全集成的核心。我们希望我们的发现将为SZ的分子靶点和早期发现和干预的适当时机提供信息，可能是对治疗耐药的亚群。此外，通过研究SZ特定认知维度背后的回路和行为机制，我们希望对SZ以外的神经发育起源的成人起病的研究和治疗做出贡献。

 DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a debilitating disorder with onset in young adulthood, with profound impact on the individual and society. Since 2008, we have made multidisciplinary efforts for this important medical question under the P20 and P50 support mechanisms. Based on our published works, promising preliminary results, and refined experimental strategies, we now conceptualize a new collaborative, hypothesis-driven research strategy towards a mechanistic understanding of SZ and related conditions. Through our past studies, we have obtained outcomes in five major areas: (i) microtubule-associated pathway as a developmental driver for the pathophysiology of SZ after puberty; (ii) changes in stress-associated molecules in SZ patients, particularly in early stages of the disease; (iii) aberrant cortical maturation in adolescence: potential gene-environment interactions during a critical period; (iv) neurocircuitry-guided behavioral characterization of mouse models associated with SZ; and (v) technological development in the analysis of RNA-sequencing data. Based on our own preliminary data as well as information published by other groups, we plan to address the following hypotheses in the coming five years: (a) genetic risks for SZ (or subset of SZ) elicit "mild" deficits during early brain development; (b) such deficits precipitate more prominent molecular and circuitry-related alterations later during adolescence; (c) stress-associated molecules activated during adolescence drive asymptomatic, vulnerable brains to a symptomatic, pathological state, directly affecting excitatory-inhibitory (E-I) imbalance; (d) such transitions are further exacerbated by psychosocial stressors in adolescence; and (e) intervention in the stress-associated transition is a key treatment strategy for SZ. To validate these hypotheses, we propose the following three Aims: (1) to define the contribution of genes encoding microtubule-associated proteins ("microtubule" genes) to SZ pathophysiology, in particular for a subset of SZ in which neurodevelopmental implications may be stronger; (2) to define how genetic risks in "microtubule" genes in early development precipitate changes in the prefrontal cortex (PFC) after puberty and how adolescent social stress may exacerbate such changes; and (3) to study how stress-associated molecules directly affect and impair the neural substrates that lead to E-I imbalance in adolescence, resulting in cognitive dysfunction in young adulthood, and how stressors during adolescence exacerbate these changes. To address these questions, we propose 3 projects and 3 cores that are fully integrated. We hope that our findings will inform molecular targets and appropriate timing for early detection and intervention for SZ, possibly for a treatment-resistant subset. Furthermore, by studying the circuitry and behavioral mechanisms underlying specific cognitive dimensions in SZ, we hope to contribute towards studies and treatment of adult-onset disorders with neurodevelopmental origins beyond SZ.