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The Nigral Molecular Clock and Vulnerability to Neurodegeneration

黑质分子钟和神经退行性疾病的脆弱性

基本信息

批准号：
10383744
负责人：
Rita Marie Cowell
金额：
$ 47.36万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383744
关键词：
ARNTL gene Age Aging Animal Model Attenuated Autophagocytosis Bacterial Artificial Chromosomes Behavioral Calcium Cells Cessation of life Characteristics Circadian Dysregulation Data Disease Disease Progression Doxycycline Electrophysiology (science)Evaluation Fluorescent in Situ Hybridization Frequencies Functional disorder Future Gene Expression Genetic Transcription Homeostasis Image Impairment Lewy Bodies Luciferases Maintenance Mediating Metabolism Midbrain structure Mitochondria Modeling Molecular Movement Disorders Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Periodicity Phenotype Physiological Population Prevention Prevention strategy Process Proteins Role Sodium Substantia nigra structure Synapses System Techniques Testing Tetanus Helper Peptide Time Transcriptional Regulation Transgenic Mice Transgenic Organisms Variant alpha synuclein behavioral impairment cell injury circadian circadian pacemaker design dopaminergic neuron experimental study insight molecular clock motor behavior motor impairment mouse model mouse synuclein alpha neuron loss neurotoxicity novel overexpression pars compacta programs protein aggregation regenerative single molecule stressor suprachiasmatic nucleus synuclein tool trafficking

项目摘要

Dopaminergic neurons of the substantia nigra are particularly susceptible to dysfunction and loss with aging and disease. A potential contributor to this vulnerability is the requirement for the maintenance of intrinsic pacemaking activity. However, little is known about how this pacemaking activity is regulated in physiological and pathological states. Understanding how nigral neurons maintain their firing rate and adapt to cellular stressors has the potential to reveal novel pathways for prevention of cellular damage and death. In this application, we are proposing to test the novel hypotheses that the molecular clock is a key regulator of pacemaking activity and other processes required for normal function of dopaminergic neurons and that disruption of this clock contributes to cell dysfunction and death in models of Parkinson Disease (PD). In support of these hypotheses, we have found that dopaminergic neuron firing rate varies with time of day and that this variation is abolished in mice with midbrain-specific deletion of the obligate transcriptional regulator of circadian function, Bmal1. Furthermore, we have found day/night differences in the expression of genes involved in pacemaking activity in the substantia nigra, suggesting that pathways important for nigral function may be regulated at the transcriptional level by the molecular clock. Interestingly, we have discovered alpha synuclein mouse models of PD display disrupted day/night differences in pacemaking activity, leading to the hypothesis that the impairment of circadian-regulated processes could contribute to neuronal dysfunction and death in disease. In Aim 1, experiments are designed to determine the mechanisms by which the molecular clock regulates dopaminergic neuron function at the transcriptional, electrophysiological, and behavioral levels, using recently developed tools to evaluate molecular clock rhythmicity and transcription in a cell-specific way. In Aim 2, experiments will utilize approaches to reset the molecular clock in a time-of-day-dependent manner in mice with α-synuclein- induced pathology to determine the role for circadian dysregulation in the progression of α-synuclein-mediated neurotoxicity and behavioral impairment. Altogether, these experiments have the potential to reveal a novel regulatory mechanism of nigral function and vulnerability and could give critical insight into disease progression and pathogenesis.

黑质多巴胺能神经元特别容易随着年龄的增长而功能障碍和丧失