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

• 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
• 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

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、奖励和情绪相关行为，其变性/功能障碍与帕金森病（PD）和精神分裂症等主要脑部疾病相关。因此，了解mDA神经元在健康和疾病中的发育、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Pitx 3的作用和调控。我们发现Wnt 1-Lmx 1a形成了一个自动调节通路，导致诱导关键转录因子Nurr 1和Pitx 3。值得注意的是，这些研究揭示了控制mDA神经元发育的两个主要途径（即，Shh-FoxA 2和Wnt 1-Lmx 1a）在Nurr 1上合并，突出了Nurr 1对mDA神经元发育/维持的重要作用。事实上，最近的研究表明，Nurr 1不仅对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。Nurr 1是一种孤儿核受体，被称为配体非依赖性组成型活性核受体。然而，引人注目的是，我们最近发现了可以直接与Nurr 1的配体结合结构域相互作用的小分子，刺激其对比鲜明的双重功能;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。基于这些有希望的数据识别潜在的合成配体/激动剂的Nurr 1，我们假设，Nurr 1可能是一个“通过”核受体，可能存在一个内源性Nurr 1配体。此外，Nurr 1的多种功能（例如，反式激活、反式阻遏或无明显功能）似乎取决于细胞环境，这可能由细胞特异性Nurr 1相互作用因子决定。为了解决这些假设，我们将系统地研究对比的双重功能的Nurr 1在没有和激动剂分子的存在下，并将确定和表征多蛋白复合物与Nurr 1在不同的细胞环境和“推定的”内源性配体（S）。我们的提议非常新颖和创新，将为Nurr 1在mDA神经元中的功能作用提供新的见解，可能会导致我们对Nurr 1在mDA神经生物学中的功能作用的理解范式转变，以及DA相关脑部疾病的未来治疗开发。