Molecular specification of dopaminergic neuron diversity

多巴胺能神经元多样性的分子规范

基本信息

批准号：
10585657
负责人：
Benjamin R Arenkiel
金额：
$ 59.37万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585657
关键词：
Adopted Basic Science Biochemical Biological Assay Biology Brain Brain region Catecholamines Cells Coupling Data Development Diabetic Retinopathy Disease Disease model Dopamine Dopaminergic Cell Endowment Etiology Eye Generations Genetic Goals Histologic Interneurons Lead Location Maps Mediating Mental disorders Midbrain structure Molecular Molecular Target Mus Neuromodulator Neurons Parkinson Disease Pathology Pathway interactions Pattern Phosphotransferases Play Population Production Property Protein-Serine-Threonine Kinases Public Health Regulation Retina Role STK11 gene Signal Transduction Specific qualifier value Substantia nigra structure System Testing Time Ventral Tegmental Area Viral Vision Visual Visual System Work cell type dopaminergic neuron gain of function improved outcome inhibitory neuron interest loss of function mutant nerve stem cell nervous system disorder neural neurogenetics neuron development neuron loss neuroregulation novel novel therapeutics preservation programs temporal measurement transcriptomics

项目摘要

PROJECT SUMMARY Dopamine is produced by a small but impactful subset of neurons in the eye and brain. Because this neuromodulator plays a critical role in a host of mental illnesses and diseases, it is vital to understand how dopamine neuron subsets are established and maintained. Our preliminary data show that the serine-threonine kinase LKB1 is required to restrict the number of dopaminergic neurons in the retina. In addition, we identify new dopaminergic cell subsets and show that LKB1 is cell-intrinsically required in inhibitory interneurons to modulate dopamine neuron diversity using molecular and neurogenetic approaches. This is a compelling result because factors that control the number and type of neurons that produce dopamine have remained elusive. To understand how LKB1 regulates dopamine neuron diversity, we have devised a strategy encompassing neural identity and connectivity mapping, cell-type specific intersectional genetic and viral strategies, molecular and biochemical studies, and functional analysis. We propose three aims. In Aim 1, we ask whether LKB1 is spatially and temporally sufficient to instruct dopamine neuron diversity by modulating this kinase in specific locations and at particular times. In Aim 2, we identify the mechanism through which LKB1 functions and test the hypothesis that LKB1-AMPK signaling plays a critical role. In Aim 3, we extend our analysis to the midbrain to test whether LKB1 is similarly required in this disease-relevant brain region to limit dopamine neuron diversity. Identifying a kinase pathway that precisely controls dopamine neuron diversity is surprising, so completing these aims will markedly advance our understanding of how dopaminergic neurons are endowed with their unique properties. In addition, these results will provide new therapeutic avenues for restoring dopamine production in the context of disease.

项目概要多巴胺是由眼睛和大脑中一小部分但有影响力的神经元产生的。因为这个神经调节剂在许多精神疾病和疾病中起着至关重要的作用，了解它是如何发挥作用至关重要的建立并维持多巴胺神经元亚群。我们的初步数据表明，丝氨酸-苏氨酸需要激酶 LKB1 来限制视网膜中多巴胺能神经元的数量。此外，我们还确定新的多巴胺能细胞亚群，并表明 LKB1 是抑制性中间神经元细胞本质上所必需的使用分子和神经遗传学方法调节多巴胺神经元多样性。这是一个令人信服的结果因为控制产生多巴胺的神经元数量和类型的因素仍然难以捉摸。为了了解 LKB1 如何调节多巴胺神经元多样性，我们设计了一种策略，包括神经身份和连接图谱、细胞类型特异性交叉遗传和病毒策略、分子和生化研究以及功能分析。我们提出三个目标。在目标 1 中，我们询问 LKB1 是否是在空间和时间上足以通过以特定方式调节该激酶来指示多巴胺神经元多样性地点和特定时间。在目标 2 中，我们确定了 LKB1 发挥作用的机制并测试 LKB1-AMPK 信号传导发挥关键作用的假设。在目标 3 中，我们将分析扩展到中脑测试该疾病相关大脑区域是否同样需要 LKB1 来限制多巴胺神经元多样性。鉴定出精确控制多巴胺神经元多样性的激酶途径是令人惊讶的，所以完成这些目标将显着增进我们对多巴胺能神经元如何被赋予的理解以其独特的性能。此外，这些结果将为恢复功能提供新的治疗途径。疾病背景下多巴胺的产生。