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Gene-Environment Interactions for Cortical Development and Schizophrenia

皮质发育和精神分裂症的基因-环境相互作用

基本信息

批准号：
9978127
负责人：
AKIRA SAWA
金额：
$ 183.35万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-12 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978127
关键词：
Address Adolescence Adolescent Adult Affect Animal Behavior Animal Model Area Behavior Behavioral Behavioral Mechanisms Bioinformatics Biological Biometry Brain Cell model Cells Clinical Cognitive Collaborations Data Development Dimensions Disease Early Diagnosis Early Intervention Electrophysiology (science)Functional disorder Future Genes Genetic Genetic Risk Histologic Human Human Genetics Impaired cognition Impairment Individual Intervention Lead Medical Memory impairment Mental disorders Methods Microtubule-Associated Proteins Microtubules Molecular Molecular Profiling Molecular Target Mus Neurobehavioral Manifestations Neurons Onset of illness Outcome Pathologic Pathway interactions Patients Pattern Pre-Clinical Model Prefrontal Cortex Prospective cohort Psychiatrist Puberty Publishing RNA analysis Refractory Research Resistance Resources Risk Role Sampling Schizophrenia Short-Term Memory Social isolation Societies Solid Stress Symptoms Work base critical period data resource defined contribution gene environment interaction human tissue innovation mouse model multidisciplinary neural circuit psychosocial public health relevance relating to nervous system social stress stressor transcriptome sequencing treatment strategy young adult

项目摘要

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.

描述（由申请人提供）：精神分裂症（SZ）是一种在青年期发病的衰弱性疾病，对个人和社会产生深远影响。自2008年以来，我们在20常和50常支持机制下为这一重要的医学问题作出了多学科努力。基于我们发表的作品，有前途的初步结果，和完善的实验策略，我们现在概念化一个新的合作，假设驱动的研究策略，对SZ和相关条件的机械理解。通过我们过去的研究，我们在五个主要领域取得了成果：（i）微管相关通路作为青春期后SZ病理生理学的发育驱动因素;（ii）SZ患者中应激相关分子的变化，特别是在疾病的早期阶段;（iii）青春期异常皮质成熟：关键时期潜在的基因-环境相互作用;（iv）青春期发育异常皮质成熟：关键时期潜在的基因-环境相互作用。（iv）SZ相关小鼠模型的神经回路引导行为表征;以及（v）RNA测序数据分析的技术开发。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的遗传风险（B）这种缺陷在青春期后期沉淀更显著的分子和回路相关的改变;（c）在青春期激活的应激相关分子将无症状的、脆弱的大脑驱动到有症状的病理状态，直接影响兴奋-抑制（E-I）失衡; 青春期的社会心理压力会进一步加剧这种过渡;（e）干预与压力相关的过渡是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的贡献（“微管”基因）与SZ病理生理学的关系，特别是对于其中神经发育影响可能更强的SZ子集;（2）确定早期发育中“微管”基因的遗传风险如何促使前额叶皮层（PFC）发生变化（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失衡的神经基质，从而导致年轻成年期的认知功能障碍，以及青春期的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。我们希望我们的研究结果将为SZ的早期检测和干预提供分子靶点和适当的时机，可能是治疗抵抗的子集。此外，通过研究特定的认知层面在SZ的电路和行为机制，我们希望有助于研究和治疗成人发病的疾病与神经发育起源超越SZ。

项目成果

期刊论文数量（87）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia.

DOI：
10.1016/j.nbd.2012.07.005
发表时间：
2012-12
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Severance EG;Gressitt KL;Halling M;Stallings CR;Origoni AE;Vaughan C;Khushalani S;Alaedini A;Dupont D;Dickerson FB;Yolken RH
通讯作者：
Yolken RH

Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives.

抗治疗精神分裂症：临床，生物学和治疗视角。