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）神经元严格控制自主运动、奖赏和情绪相关行为，其退化/功能障碍与帕金森病（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发育、存活和功能的分子机制至关重要。在上一个资助周期中，我们研究了关键外在因子和内在转录因子的调控网络，这些因子关键控制 mDA 神经元发育，重点关注 Pitx3 的作用和调控。我们发现 Wnt1-Lmx1a 形成一条自动调节途径，导致关键转录因子 Nurr1 和 Pitx3 的诱导。值得注意的是，这些研究揭示了控制 mDA 神经元发育的两条主要途径（即 Shh-FoxA2 和 Wnt1-Lmx1a）在 Nurr1 上合并，突出了 Nurr1 对于 mDA 神经元发育/维持的重要作用。事实上，最近的研究表明，Nurr1 不仅对于 mDA 神经元的发育和长期维持（通过反式激活功能）至关重要，而且对于保护它们免受炎症诱导的死亡（通过炎症基因的反式抑制）也至关重要。 Nurr1 是一种孤儿核受体，被称为配体独立的组成型活性核受体。然而，引人注目的是，我们最近发现了可以直接与 Nurr1 的配体结合域相互作用的小分子，刺激其对比的双重功能；进一步激活 mDA 神经元功能并进一步反式抑制小胶质细胞中炎症基因的表达。基于这些确定 Nurr1 潜在合成配体/激动剂的有希望的数据，我们假设 Nurr1 可能是“过继”核受体，并且可能存在内源性 Nurr1 配体。此外，Nurr1 的多种功能（例如反式激活、反式抑制或无明显功能）似乎取决于细胞环境，这可能由细胞特异性 Nurr1 相互作用因子决定。为了解决这些假设，我们将系统地研究 Nurr1 在不存在和存在激动剂分子的情况下的双重功能，并将鉴定和表征不同细胞环境中与 Nurr1 和“假定的”内源配体相关的多蛋白复合物。我们的提议非常新颖和创新，将为我们对 Nurr1 在 mDA 神经元中的功能作用提供新的见解，有可能导致我们对 Nurr1 在 mDA 神经生物学中的功能作用的理解发生范式转变，以及 DA 相关脑部疾病的未来治疗发展。