Cross modal integration of molecular and physiological networks in ASD (2/2)

ASD 中分子和生理网络的跨模式整合 (2/2)

基本信息

  • 批准号:
    9479643
  • 负责人:
  • 金额:
    $ 84.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-21 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

Genetic approaches have been successful in identifying causal genetic factors, both common and rare, that contribute to risk for autism spectrum disorder (ASD), providing a crucial starting point for mechanistic neurobiological investigations. However, moving towards an integrated mechanistic understanding of ASD at a molecular, cellular, and circuit level faces substantial challenges, such as extreme genetic heterogeneity and the lack of causal frameworks with which to connect different levels of analysis of nervous system function in model systems or patients. Nearly a decade ago, we reasoned that gene and protein networks would provide an organizing framework for understanding heterogeneous psychiatric disease genetic risk in a unified context and inform disease modeling; indeed there is now substantial evidence supporting convergence of major effect risk genes during mid-fetal cortical development. Furthermore, related functional genomic studies, including in those with a major gene form of ASD (dup)15q11-13, show shared patterns of transcriptional and chromatin dysregulation in post-mortem ASD brain, further supporting biological convergence. Where and how this occurs, and what biological mechanism(s) it reflects is not known. To address this, we propose an ambitious project that addresses several major challenges in establishing causal linkages between genetic risk and CNS structure and function in ASD. The work proposed in this multi-PI U01 involves a team of four principal investigators and co-investigators from UCLA and Stanford with the expertise necessary to perform this work using state of the art methodologies, ranging from developing and characterizing in vitro models of human brain development, stem cells, physiology, genomics, physics, and behavior. Through close collaboration, we will develop and analyze in vitro human stem cell based models that are differentiated from induced pluripotent stem cells and assembled into organized 3D brain cultures called human forebrain spheroids (hFS). These hFS contain the major cell classes of the developing forebrain, including progenitors, radial glia, cortical interneurons, glutamatergic neurons, and non-reactive astrocytes, and form functional synapses. We will model the effects of six major effect ASD risk loci in hFS with molecular, genomic, and physiological analyses to assess convergence at each level of analysis. We will also conduct comparisons of physiology using three rodent models based on the same genes modeled in vitro with the aim of integrating phenotypes to develop predictive models and compare with in vivo rodent models. We will analyze the relationship of molecular alterations and basic cellular and synaptic features with potential emergent or dynamic network features in control-derived hFS and compare these features with hFS harboring ASD risk mutations and test a subset of causal relationships based on network model predictions. Completion of these aims will lead to a more clear understanding of the power and limitations of model systems and computational models, while uncovering potential areas of convergence in different genetic forms of ASD.
遗传方法已成功地识别了常见和罕见的致病遗传因素, 导致自闭症谱系障碍 (ASD) 的风险,为机械性治疗提供了重要的起点 神经生物学研究。然而,朝着对自闭症谱系障碍 (ASD) 的综合机制理解迈进 分子、细胞和电路水平面临着巨大的挑战,例如极端的遗传异质性 以及缺乏连接不同层次的神经系统分析的因果框架 在模型系统或患者中发挥作用。大约十年前,我们推断基因和蛋白质网络 将为理解异质性精神疾病遗传风险提供一个组织框架 统一背景并为疾病建模提供信息;事实上,现在有大量证据支持 胎儿中期皮质发育期间主要效应风险基因的趋同。此外,相关功能 基因组研究,包括那些具有 ASD (dup)15q11-13 主要基因形式的研究,显示了以下共同的模式: 死后 ASD 大脑中的转录和染色质失调,进一步支持生物学 收敛。这种现象在哪里、如何发生,以及它反映了什么生物机制尚不清楚。到 为了解决这个问题,我们提出了一个雄心勃勃的项目,解决建立因果关系的几个主要挑战 ASD 遗传风险与中枢神经系统结构和功能之间的联系。本次多PI U01中提出的工作 包括来自加州大学洛杉矶分校和斯坦福大学的四名主要研究人员和联合研究人员组成的团队,具有专业知识 使用最先进的方法来完成这项工作是必要的,从开发和 表征人脑发育、干细胞、生理学、基因组学、物理学和 行为。通过密切合作,我们将开发和分析基于体外人类干细胞的模型 从诱导多能干细胞中分化出来并组装成有组织的 3D 脑培养物 称为人类前脑球体(hFS)。这些 hFS 包含发育中的主要细胞类别 前脑,包括祖细胞、放射状胶质细胞、皮质中间神经元、谷氨酸能神经元和非反应性神经元 星形胶质细胞,并形成功能性突触。我们将对 hFS 中六个主要影响 ASD 风险位点的影响进行建模 通过分子、基因组和生理分析来评估每个分析级别的收敛性。我们将 还使用基于体外建模的相同基因的三种啮齿动物模型进行生理学比较 目的是整合表型来开发预测模型并与体内啮齿动物模型进行比较。 我们将分析分子改变以及基本细胞和突触特征与潜在的关系 控制衍生的 hFS 中的紧急或动态网络特征,并将这些特征与 hFS 隐藏进行比较 ASD 风险突变并根据网络模型预测测试因果关系的子集。完成 对这些目标的理解将导致对模型系统的力量和局限性有更清晰的理解 计算模型,同时揭示自闭症谱系障碍不同遗传形式的潜在趋同领域。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sergiu Pasca其他文献

Sergiu Pasca的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Sergiu Pasca', 18)}}的其他基金

Role of L-type Calcium Channels in Human Interneuron Migration and Integration
L型钙通道在人中间神经元迁移和整合中的作用
  • 批准号:
    9427931
  • 财政年份:
    2018
  • 资助金额:
    $ 84.06万
  • 项目类别:
Role of L-type Calcium Channels in Human Interneuron Migration and Integration
L型钙通道在人中间神经元迁移和整合中的作用
  • 批准号:
    9762226
  • 财政年份:
    2018
  • 资助金额:
    $ 84.06万
  • 项目类别:
Role of L-type Calcium Channels in Human Interneuron Migration and Integration
L型钙通道在人中间神经元迁移和整合中的作用
  • 批准号:
    9918982
  • 财政年份:
    2018
  • 资助金额:
    $ 84.06万
  • 项目类别:
Role of L-type Calcium Channels in Human Interneuron Migration and Integration
L型钙通道在人中间神经元迁移和整合中的作用
  • 批准号:
    10391481
  • 财政年份:
    2018
  • 资助金额:
    $ 84.06万
  • 项目类别:
Cross modal integration of molecular and physiological networks in ASD (2/2)
ASD 中分子和生理网络的跨模式整合 (2/2)
  • 批准号:
    9753368
  • 财政年份:
    2017
  • 资助金额:
    $ 84.06万
  • 项目类别:
Cross modal integration of molecular and physiological networks in ASD (2/2)
ASD 中分子和生理网络的跨模式整合 (2/2)
  • 批准号:
    10225520
  • 财政年份:
    2017
  • 资助金额:
    $ 84.06万
  • 项目类别:
Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
通过在体外对人脑进行逐个改造,深入了解精神疾病。
  • 批准号:
    10222534
  • 财政年份:
    2015
  • 资助金额:
    $ 84.06万
  • 项目类别:
Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
通过在体外对人脑进行逐个改造,深入了解精神疾病。
  • 批准号:
    10645198
  • 财政年份:
    2015
  • 资助金额:
    $ 84.06万
  • 项目类别:
Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
通过在体外对人脑进行逐个改造,深入了解精神疾病。
  • 批准号:
    10418740
  • 财政年份:
    2015
  • 资助金额:
    $ 84.06万
  • 项目类别:
Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
通过在体外对人脑进行逐个改造,深入了解精神疾病。
  • 批准号:
    8957296
  • 财政年份:
    2015
  • 资助金额:
    $ 84.06万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 84.06万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了