Targeting Mitochondrial Function to Develop Novel Therapies for Neurodevelopmental Disorders

针对线粒体功能开发神经发育障碍的新疗法

基本信息

项目摘要

ABSTRACT We will identify potential new pharmacological therapies targeted to improve mitochondrial function in a class of cerebral cortical neurons thought to be compromised in multiple neurodevelopmental disorders. We have shown that mitochondrial metabolism is disrupted in layer 2/3 Projection Neurons (PNs) in the LgDel mouse model of 22q11.2 Deletion Syndrome, a syndromic neurodevelopmental disorder. We have also demonstrated that this disruption apparently accounts for quantitative differences in association cortical connectivity correlated with cognitive behavioral deficits in LgDel mice. Finally, we showed that a free radical scavenger that influences mitochondrial function, N-acetyl cysteine (NAC), can reverse these molecular, cellular and behavioral deficits. We will now assess the capacity of multiple mitochondrial targeted pharmacological compounds, as well as known mitochondria-targeted drugs, to modulate LgDel Layer 2/3 PN mitochondrial metabolism and its influences on layer 2/3 PN homeostasis. In Specific Aim 1, we will evaluate compound activity in a validated, homogeneous layer 2/3 PN in vitro assay using the Agilent Seahorse Metabolic Analyzer to measure key aspects of mitochondrial function. Candidate compounds that restore LgDel mitochondrial dysfunction toward WT, without disrupting WT mitochondrial function, will be further validated for their capacity to diminish aberrant mitochondrial reactive oxygen species (ROS) levels and restore dendritic and axonal growth in LgDel layer 2/3 PNs. To provide additional interpretative resolution of the mechanistic precision of these compounds, in Specific Aim 2 we will perform a parallel transcriptome comparison of LgDel versus WT Layer 2/3 PNs in vitro to identify pathways whose transcriptional regulation is altered due to mitochondrial dysfunction and diminished growth in developing Layer 2/3 PNs targeted by neurodevelopmental pathology. We will further contrast this data with the transcriptome profile of LgDel layer 2/3 PNs treated with NAC, whose metabolic and growth-restoring activity we have previously demonstrated. Thus, compounds identified in this screen will be validated for specificity, targeted cellular activity, and placed in context of differentially regulated transcriptional pathways sensitive to altered mitochondrial function. These pathways underlie diminished neuron growth that contributes to neurodevelopmental cortical circuit pathology. Thus, our experiments identify potential candidates for further development of mitochondria-based therapies and a molecular mechanistic framework for rational design of precisely targeted new drugs to correct molecular and cellular pathology associated with cortical neuron and circuits compromised in multiple neurodevelopmental disorders.
摘要

项目成果

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ANTHONY S LAMANTIA其他文献

ANTHONY S LAMANTIA的其他文献

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{{ truncateString('ANTHONY S LAMANTIA', 18)}}的其他基金

Targeting Mitochondrial Function to Develop Novel Therapies for Neurodevelopmental Disorders
针对线粒体功能开发神经发育障碍的新疗法
  • 批准号:
    10330605
  • 财政年份:
    2021
  • 资助金额:
    $ 24万
  • 项目类别:
Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia
小儿吞咽困难的病理学、发育起源和预防
  • 批准号:
    8856405
  • 财政年份:
    2015
  • 资助金额:
    $ 24万
  • 项目类别:
Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia
小儿吞咽困难的病理学、发育起源和预防
  • 批准号:
    9567053
  • 财政年份:
    2015
  • 资助金额:
    $ 24万
  • 项目类别:
Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia
小儿吞咽困难的病理学、发育起源和预防
  • 批准号:
    9234411
  • 财政年份:
    2015
  • 资助金额:
    $ 24万
  • 项目类别:
Developmental mechanisms for pediatric dysphagia
小儿吞咽困难的发育机制
  • 批准号:
    9567059
  • 财政年份:
    2015
  • 资助金额:
    $ 24万
  • 项目类别:
Administration and Training
行政及培训
  • 批准号:
    8856410
  • 财政年份:
    2015
  • 资助金额:
    $ 24万
  • 项目类别:
Specification of Peripheral Olfactory Stem Cells
外周嗅觉干细胞的规格
  • 批准号:
    8912894
  • 财政年份:
    2011
  • 资助金额:
    $ 24万
  • 项目类别:
Specification of Peripheral Olfactory Stem Cells
外周嗅觉干细胞的规格
  • 批准号:
    8336866
  • 财政年份:
    2011
  • 资助金额:
    $ 24万
  • 项目类别:
Specification of Peripheral Olfactory Stem Cells
外周嗅觉干细胞的规格
  • 批准号:
    8247915
  • 财政年份:
    2011
  • 资助金额:
    $ 24万
  • 项目类别:
Specification of Peripheral Olfactory Stem Cells
外周嗅觉干细胞的规格
  • 批准号:
    8519102
  • 财政年份:
    2011
  • 资助金额:
    $ 24万
  • 项目类别:

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