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：
10330605
负责人：
ANTHONY S LAMANTIA
金额：
$ 20万
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/10330605
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 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 drug discovery effective therapy experimental study gene network 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 rational design 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.

抽象的我们将确定旨在改善类中线粒体功能的潜在新药理疗法被认为在多种神经发育障碍中被损害的脑皮质神经元的。我们有表明线粒体代谢在LGDEL小鼠的第2/3层投影神经元（PNS）中被破坏 22q11.2缺失综合征的模型，一种综合征神经发育障碍。我们也证明了这种中断显然是相关皮质连通性的定量差异与LGDEL小鼠的认知行为缺陷相关。最后，我们证明了一个自由基的清道夫影响线粒体功能N-乙酰基半胱氨酸（NAC）可以逆转这些分子，细胞和行为不足。现在，我们将评估多个线粒体靶向药理的能力化合物以及已知的线粒体靶向药物，以调节LGDEL层2/3 Pn线粒体代谢及其对第2/3层PN稳态的影响。在特定目标1中，我们将评估化合物使用Agilent Seahorse代谢分析仪，在经过验证的均质层2/3 PN的均匀层中的活性测量线粒体功能的关键方面。恢复LGDEL线粒体的候选化合物对WT的功能障碍，而不会破坏WT线粒体功能，将进一步验证其能力减少异常线粒体活性氧（ROS）水平并恢复树突状和轴突 LGDEL层2/3 PNS的生长。提供机械精度的其他解释性分辨率这些化合物，在特定目标2中，我们将进行LGDEL与WT的平行转录组比较体外2/3层PNS，以识别因线粒体而改变的转录调节的途径神经发育病理靶向的2/3 PN层的功能障碍和生长减少。我们将进一步将这些数据与用NAC处理的LGDEL层的转录组曲线进行对比我们以前已经证明的代谢和生长恢复活性。因此，在此确定的化合物屏幕将得到特异性，靶向细胞活性的验证，并将其放置在差异调节的背景下转录途径对改变的线粒体功能敏感。这些途径下降了神经元的生长有助于神经发育皮质回路病理。因此，我们的实验确定了进一步发展线粒体疗法和分子机械的潜在候选者精确靶向新药的合理设计框架以纠正分子和细胞病理学与在多种神经发育障碍中受损的皮质神经元和电路有关。