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

描述(申请人提供)：中脑多巴胺(MDA)神经元关键控制自主运动、奖励和情绪相关行为，它们的退化/功能障碍与帕金森氏病(PD)和精神分裂症等主要大脑疾病有关。因此，了解健康和疾病中丙二醛神经元的发育、存活和功能的分子机制是至关重要的。在上一个资金周期中，我们研究了关键的外在因素和内在转录因子的调控网络，这些因素对丙二醛神经元的发育至关重要，重点是Pitx3的作用和调控。我们发现Wnt1-Lmx1a形成了一条自我调节通路，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丙二醛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的S在丙二醛神经元发育/维持中的重要作用(S)。事实上，最近的研究表明，Nurr1不仅对丙二醛神经元的发育和长期维持(通过反式激活功能)至关重要，而且对于它们免受炎症诱导的死亡(通过反式抑制炎症基因)也是至关重要的。Nurr1是一种孤儿核受体，被认为是一种非配体依赖性的活性核受体。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，刺激其截然不同的双重功能；更重要的是，它激活了MDA神经元功能，并进一步反式抑制了小胶质细胞中炎症基因的表达。基于这些有希望的数据确定了Nurr1的潜在合成配体/激动剂，我们假设Nurr1可能是“被采用的”核受体，并且可能存在内源性的Nurr1配体。此外，Nurr1‘S的多种功能(如反式激活、反式抑制或无明显功能)似乎依赖于细胞环境，这可能由细胞特异性的Nurr1相互作用因子(S)决定。为了解决这些假设，我们将系统地研究在没有和存在激动剂分子的情况下Nurr1的双重功能的对比，并将在不同的细胞环境中鉴定和表征与Nurr1相关的多蛋白复合体和“假定的”内源性配体(S)。我们的建议是非常新颖和创新的，将对Nurr1在丙二醛神经元中的功能角色提供新的见解，可能导致我们对Nurr1的S在丙二醛神经生物学和未来DA相关脑疾病的治疗发展中的功能角色的理解的范式转变。

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.