Inhibitors of Synaptogenesis and Mental Health

突触发生和心理健康的抑制剂

基本信息

  • 批准号:
    10468640
  • 负责人:
  • 金额:
    $ 49.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-24 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Mounting evidence suggests that many neuropsychiatric disorders have a developmental origin with a strong genetic underpinning. A large number of allelic variants has been identified that associate with mental illness. While genetic discoveries are a crucial first step, the next major challenge is to define the biochemical pathways altered by disease alleles and to develop a more nuanced understanding of how these dysfunctional pathways disrupt brain function relevant to disease symptomatology. Of interest, mutations in members of the SEMAPHORIN (SEMA) family of axon guidance molecules, and their receptors, the PLEXINS (PLXN) carry varying genetic risks for mental illness. Allelic variants of SEMA5A and its receptor PLXNA2 associated with mood disorders cause reduced gene expression. To explore the underlying biology of how reduced SEMA5A/PLXNA2 expression may contribute to mental illness, we use Plxna2 transgenic mice as an experimental system. Morphological studies with Sema5a and Plxna2 mutant mice identified distinct anatomical phenotypes: defects in migration of early-born dentate granule cells (GCs) progenitors from the primary neuroepithelium to the dentate gyrus (DG) and an increase in spine synapse density in mature GCs in the DG. Adult Plxna2 mice exhibit gene-dosage and sex-specific behavioral defects in episodic memory, sensorimotor gating, and sociability; traits commonly observed in psychiatric disorders including Schizophrenia. For a deeper understanding of how Plxna2 deficiency may contribute to behavioral phenotypes, we used gene editing to disrupt the GTPase-activating protein (GAP) domain in the PlxnA2 cytoplasmic region. Loss of PlxnA2-GAP enzymatic activity impairs Rap1-GTPase dependent GC progenitor migration and leads to supernumerary spine synapses in mature GC. Moreover, PlxnA2-GAP deficiency disrupts episodic memory and sensorimotor gating. To probe deeper into how impaired Sema5A/PlxnA2-GAP/Rap1 signaling leads to behavioral defects, we used a proteomics-based approach and identified novel PlxnA2 interacting proteins. In the current application we propose a multidisciplinary approach comprised of recently developed biochemical tools, electrophysiological techniques, conditional gene ablation and mouse behavior. SPECIFIC AIM 1 is aimed at the characterization of novel mechanisms that regulate Sema5A-PlxnA2 signaling, including the guanine nucleotide exchange factors (GEFs) that antagonize PlxnA2-GAP activity. SPECIFIC AIM 2 builds on our observation that forebrain specific ablation of Plxna2 mimics behavioral defects observed in Plxna2 germline null mice. We pursue a mouse genetic approach to identify developmental epochs of vulnerability and the neural substrate associated with impaired behaviors in Plxna2-/- and Plxna2-GAP deficient mice. Genetic studies will be complemented by electrophysiological recordings, histological analyses and high- resolution magnetic resonance imaging. Studies are aimed at determining where and when Plxna2-GAP function is required during brain development to ensure normal behavior in adulthood.
越来越多的证据表明,许多神经精神疾病有一个发育的起源与强烈的

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 }}

Roman Jeno Giger其他文献

Roman Jeno Giger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('Roman Jeno Giger', 18)}}的其他基金

Development of live-cell probes to investigate tubulin post-translational modifications in neuronal regeneration
开发活细胞探针来研究神经元再生中微管蛋白翻译后修饰
  • 批准号:
    10648255
  • 财政年份:
    2023
  • 资助金额:
    $ 49.61万
  • 项目类别:
Inhibitors of Synaptogenesis and Mental Health
突触发生和心理健康的抑制剂
  • 批准号:
    10224879
  • 财政年份:
    2019
  • 资助金额:
    $ 49.61万
  • 项目类别:
Inhibitors of Synaptogenesis and Mental Health
突触发生和心理健康的抑制剂
  • 批准号:
    10682405
  • 财政年份:
    2019
  • 资助金额:
    $ 49.61万
  • 项目类别:
Inhibitors of Synaptogenesis and Mental Health
突触发生和心理健康的抑制剂
  • 批准号:
    10023276
  • 财政年份:
    2019
  • 资助金额:
    $ 49.61万
  • 项目类别:
Neuronal regulation of myelination
髓鞘形成的神经元调节
  • 批准号:
    8420808
  • 财政年份:
    2012
  • 资助金额:
    $ 49.61万
  • 项目类别:
Neuronal regulation of myelination
髓鞘形成的神经元调节
  • 批准号:
    8894103
  • 财政年份:
    2012
  • 资助金额:
    $ 49.61万
  • 项目类别:
Neuronal regulation of myelination
髓鞘形成的神经元调节
  • 批准号:
    8546459
  • 财政年份:
    2012
  • 资助金额:
    $ 49.61万
  • 项目类别:
Neuronal regulation of myelination
髓鞘形成的神经元调节
  • 批准号:
    8693038
  • 财政年份:
    2012
  • 资助金额:
    $ 49.61万
  • 项目类别:
Nogo Receptor Family: Novel Mechanisms to Inhibit Growth
Nogo 受体家族:抑制生长的新机制
  • 批准号:
    6822187
  • 财政年份:
    2004
  • 资助金额:
    $ 49.61万
  • 项目类别:
Nogo Receptor Family: Novel Mechanisms to Inhibit Growth
Nogo 受体家族:抑制生长的新机制
  • 批准号:
    7116772
  • 财政年份:
    2004
  • 资助金额:
    $ 49.61万
  • 项目类别:

相似海外基金

Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
  • 批准号:
    24K21101
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
  • 批准号:
    24K11201
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
  • 批准号:
    24K11281
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
  • 批准号:
    EP/Z001145/1
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Fellowship
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
  • 批准号:
    2338890
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334777
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334775
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334776
  • 财政年份:
    2024
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
  • 批准号:
    515081333
  • 财政年份:
    2023
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
  • 批准号:
    2320040
  • 财政年份:
    2023
  • 资助金额:
    $ 49.61万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了