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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

批准号：
10196091
负责人：
ANTHONY S LAMANTIA
金额：
$ 24万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196091
关键词：
Antioxidants Area Attention deficit hyperactivity disorder Behavioral Behavioral Symptoms Biological Biomass Candidate Disease Gene Cells Cerebrum Clinical Cognitive Consumption Cysteine Data Development DiGeorge Syndrome Diagnosis Diagnostic Disease Drug Targeting Foundations Free Radical Scavengers Genes Genetic Genetic Diseases Genetic Transcription Genus Hippocampus Goals Growth Homeostasis In Vitro Intellectual functioning disability Intervention Libraries Measures Metabolic Mitochondria Modeling Molecular Molecular Target Mus Neurodevelopmental Disorder Neurons Oxidative Stress Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Physiological Reactive Oxygen Species Resolution Schizophrenia Signal Transduction Specificity Syndrome Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Intervention Transcriptional Regulation associated symptom autism spectrum disorder axon growth base behavioral outcome cellular pathology cellular targeting clinical Diagnosis design drug discovery effective therapy experimental study high throughput screening improved in vitro Assay in vivo mitochondrial dysfunction mitochondrial metabolism molecular pathology mouse model neurite growth neuron development neuronal growth new therapeutic target novel novel diagnostics novel strategies novel therapeutic intervention novel therapeutics personalized diagnostics response screening targeted treatment therapeutic target trafficking transcriptome

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