Functional Roles of Nurr1 for Midbrain Dopamine Neurons in Health and Disease

Nurr1 对中脑多巴胺神经元在健康和疾病中的功能作用

基本信息

批准号：
8759085
负责人：
Kwang-Soo Kim
金额：
$ 34.56万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759085
关键词：
Acetone Address Adopted Affect Agonist Amodiaquine Astrocytes Behavior Binding Bioinformatics Biological Brain Brain Diseases Cell Culture Techniques Cell Death Cells Cessation of life Chloroquine Crystallization Data Development Disease Drug Addiction Emotions Functional disorder Funding Furuncles Future Gene Expression Genes Health Human In Vitro Inflammation Inflammatory Intrinsic factor Lead Ligand Binding Domain Ligands Maintenance Microglia Midbrain structure Modeling Molecular Moods Movement Multiprotein Complexes Mus Neurobiology Neurons Nuclear Orphan Receptor Nuclear Receptors Organ Orphan Oxidopamine Parkinson Disease Pathway interactions Play Precipitation Rattus Regulation Rewards Role Schizophrenia Signal Transduction Structure-Activity Relationship System Tissue Extracts Transactivation Ultrafiltration base cell type dopaminergic neuron embryonic stem cell in vivo innovation insight macrophage neuroinflammation neuron development neuronal survival neurotoxic novel novel therapeutics protein protein interaction receptor research study small molecule therapeutic development therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Midbrain dopaminergic (mDA) neurons critically control voluntary movement, reward, and mood-related behaviors, and their degeneration/dysfunction is associated with major brain disorders such as Parkinson's disease (PD) and schizophrenia. Thus, it is critical to understand molecular mechanisms underlying development, survival, and function of mDA neurons in health and disease. During the last funding cycle, we investigated the regulatory networks of key extrinsic factors and intrinsic transcription factors that critically control mDA neuronal development, focusing on the role and regulation of Pitx3. We found that Wnt1-Lmx1a form an autoregulatory pathway leading to induction of key transcription factors, Nurr1 and Pitx3. Notably, these studies revealed that two major pathways controlling mDA neuronal development (i.e., Shh-FoxA2 and Wnt1-Lmx1a) merge on Nurr1, highlighting Nurr1's essential role(s) for mDA neuron development/ maintenance. Indeed, recent studies showed that Nurr1 is critical not only for the development and long-term maintenance of mDA neurons (by transactivation function) but also for their protection from inflammation-induced death (through transrepression of inflammatory genes). Nurr1 is an orphan nuclear receptor and is known as a ligand-independent constitutively active nuclear receptor. Strikingly, however, we recently identified small molecules that can directly interact with the ligand binding domain of Nurr1 stimulating its contrasting dual functions; furthe activating the mDA neuronal function and further transrepressing expression of inflammatory genes in microglia. Based on these promising data identifying potential synthetic ligands/agonists of Nurr1, we hypothesize that Nurr1 may be an "adopted" nuclear receptor and that there may exist an endogenous Nurr1 ligand. Furthermore, Nurr1's diverse functions (e.g., transactivation, transrepression, or no apparent function) appear to depend upon the cellular context, which may be determined by cell-specific Nurr1-interacting factor(s). To address these hypotheses, we will systematically investigate the contrasting dual functions of Nurr1 in the absence and in the presence of agonist molecules and will identify and characterize multiprotein complexes associated with Nurr1 in different cellular contexts and the "putative" endogenous ligand(s). Our proposal is highly novel and innovative and will shed new insights into the functional roles of Nurr1 in mDA neurons, potentially leading to a paradigm-shift of our understanding of Nurr1's functional roles on mDA neurobiology and future therapeutic development of DA-related brain disorders.

描述（由申请人提供）：中脑多巴胺能（MDA）神经元严重控制自愿运动，奖励和与情绪相关的行为，其退化/功能障碍与诸如帕金森氏病（PD）和精神分裂症等主要脑部疾病有关。因此，了解MDA神经元在健康和疾病中的发展，生存和功能的分子机制至关重要。在上一个融资周期中，我们研究了关键外部因素和内在转录因子的调节网络，这些因素和内在转录因子严格控制MDA神经元发展，重点是PITX3的作用和调节。我们发现WNT1-LMX1A形成了一种自动调节途径，导致关键转录因子Nurr1和pitx3诱导。值得注意的是，这些研究表明，控制MDA神经元发育（即SHH-FOXA2和WNT1-LMX1A）的两种主要途径在Nurr1上合并，强调了Nurr1在MDA神经元开发/维持中的基本作用。实际上，最近的研究表明，Nurr1不仅对MDA神经元的发展和长期维持（通过反式激活功能）至关重要，而且对于它们免受炎症诱导的死亡（通过炎症基因的反应）的保护至关重要。 Nurr1是孤儿核受体，被称为独立于配体的组成型核受体。然而，引人注目的是，我们最近确定了可以直接与Nurr1的配体结合结构域相互作用的小分子，从而刺激其对比偶功能。在小胶质细胞中激活MDA神经元功能和进一步的炎症基因表达。基于这些有前途的数据，识别Nurr1的潜在合成配体/激动剂，我们假设Nurr1可能是一种“采用”的核受体，并且可能存在内源性Nurr1配体。此外，Nurr1的各种功能（例如，反式激活，反式或没有明显的功能）似乎取决于细胞上下文，这可能由细胞特异性的Nurr1相互作用因子（S）确定。为了解决这些假设，我们将在不存在和存在激动剂分子的情况下系统地研究NURR1的对比双重功能，并将识别和表征与Nurr1在不同细胞环境中与Nurr1相关的多蛋白络合物以及“推定的”内源性配体（S）。我们的建议是高度新颖和创新的，它将为Nurr1在MDA神经元中的功能作用提供新的见解，这可能导致我们对Nurr1在MDA神经生物学上的功能作用的理解和DA与DA相关脑疾病的未来治疗性发展的理解。