ROLE OF DOPAMINE RECEPTORS IN PRIMARY FOCAL DYSTONIAS

多巴胺受体在原发性局灶性肌张力障碍中的作用

• 批准号: 8259143
• 负责人: Morvarid Karimi
• 金额: $ 16.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259143
• 关键词: Accounting; Adult; Adverse effects; Affect; Age; Amphetamines; Award; Basal Ganglia; Binding; Brain; Cephalic; Chronic; Clinical; Clinical Skills; Complex; Corpus striatum structure; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dyskinetic syndrome; Dystonia; Etiology; Focal Dystonias; Functional disorder; Funding; Gender; Goals; Grant; Health; Human; Investigation; Involuntary Movements; Knowledge; Label; Ligands; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Mentorship; Methods; Modeling; Movement Disorders; Muscle Contraction; Mutation; Paper; Pathway interactions; Patients; Pattern; Play; Population; Positron-Emission Tomography; Posture; Property; Publishing; Raclopride; Research; Resources; Rest; Role; Secure; Seeds; Serotonin; Spiperone; Synaptic plasticity; System; Techniques; Testing; Time; Training; Translating; Universities; Validation; Washington; Work; acetylcholine transporter; arm; base; career; career development; cholinergic; design; disabling disease; effective therapy; experience; in vivo; interest; meetings; neuroimaging; neuromechanism; new therapeutic target; nonhuman primate; novel; presynaptic; programs; radioligand; receptor; receptor binding; research and development; response; treatment strategy; uptake; validation studies

DESCRIPTION (provided by applicant): This is a proposal to support my career development and research efforts in clarifying the role of dopamine receptors in primary focal dystonias. I have received clinical training in Movement Disorders under Dr. Joel Perlmutter's tutelage and participated intensively on numerous projects in his lab, as well as worked towards developing my own unique interests and funding. My long term goal is to achieve a better understanding of the basal ganglia network and its role in the pathophysiology of movement disorders with the use of neuroimaging techniques. I have access to world-class facilities at Washington University, numerous didactic courses and seminars, and excellent mentorship by Drs. Perlmutter, Mach and Schlaggar. Receiving this award would be a unique opportunity to secure protected time and the resources much needed for a goal-oriented effort. Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing abnormal postures. This disabling disease may afflict 250,000 people in the U.S. Although specific genetic defects may cause some forms of dystonia its etiology remains unknown and treatment options unsatisfactory. Conventional dystonia models incorporate abnormalities in dopaminergic pathways with main focus on D2-like receptors, but studies have yet to identify which dopamine receptor subtypes are most involved, and how these changes affect downstream functional pathways. Thus, using neuroimaging, this application will refine the current models by distinguishing whether D3 and D1-like receptors are affected, and whether abnormal receptor levels affect the functional connectivity of relevant brain networks. Most previous neuroimaging work in dystonia has focused on D2-like (D2, D3, D4) receptors. However, the ability of PET to distinguish receptor subtypes depends upon the selectivity of the radioligands. We found that striatal spiperone binding in primary focal dystonia was reduced, but this ligand also binds to 5-HT(2A) receptors. Other studies have found reduced raclopride uptake, which has a low selectivity for 5-HT(2A) but near equal selectivity for D2 and D3 receptors. Subsequently, we did not find reduced binding with a highly selective D2 ligand NMB (200-fold more selective for D2 than D3) in dystonia. These findings suggest that an abnormality of D3 receptors (D3 R) may account for these discrepancies and thus be the critical dopaminergic abnormality in dystonia. In addition it will be important to establish whether D1-like receptors are also abnormal as there is emerging evidence for the synergistic function of D1 and D3 receptors, and existing data with regard to the role of D1-like receptors in dystonia are quite limited. Finally, alterations in endogenous dopamine level could explain receptor binding abnormalities and need to be clarified. Dopaminergic pathways play a central role in mediating synaptic plasticity in striatum, and D3 R may facilitate this role through autoregulatory properties, interaction with D1-like receptors and regulatory effects on striatal dopamine level. Hence, a disturbance of striatal D3 R could perturb the function of cortico-thalamo-cerebellar circuits leading to dystonia. We will examine the integrity of these functional networks in dystonia using resting state functional connectivity MRI. We propose to test hypotheses about the critical dopaminergic abnormalities in dystonia and their consequences for functional networks in the brain using novel neuroimaging techniques. Specifically, we will determine whether adult patients with primary focal dystonia have reduced striatal D1-like binding, reduced striatal dopamine, reduced striatal D3 binding (after validating the use of the proposed D3 radioligand in nonhuman primates) and altered functional networks associated with regional dopamine binding abnormalities. This information could translate into new therapeutic targets, open new avenues of research in other populations using our novel D3 receptor ligand and refine current dystonia models. I plan to apply for an R01 toward the end of the award period using the experience and data gathered from this proposal. The R01 could include investigation of dopamine receptors and the functional connectivity in other forms of dystonia to look for commonality or differences in the pathophysiology of dystonia subtypes. Selective ligands for D2 R, D3 R and D1-like receptors could be used to investigate the pathophysiology of dyskinesias in PD given their likely role in development of this disabling side effect of PD therapy. Further, I could study whether the slow response to chronic GPi DBS in dystonia is associated with any alteration of dopamine receptor subtypes. The knowledge and experience gained from the radioligand validation for D3 R can be applied to other radioligands crucial for investigation of dystonias as well. The cholinergic system is thought to contribute to the pathophysiology of dystonia and Dr. Mach's lab is developing a ligand to label the vesicular acetylcholine transporter. I will design and perform validation studies and apply the radioligand to dystonia. In summary, my goals of applying for this career development grant are to complete the above project, to obtain substantial research and clinical skills, publish at least one first-authored paper each year, present research at national meetings on a yearly basis, and apply for an R01 by the third year of this mentored career award with the aim of developing my own independent research program.

描述（由申请人提供）：这是一项建议，旨在支持我的职业发展和研究工作，以阐明多巴胺受体在主要局部局部肌张力障碍中的作用。我在Joel Perlmutter博士的指导下接受了运动障碍的临床培训，并在他的实验室中大量参与了许多项目，并致力于发展自己的独特兴趣和资金。我的长期目标是通过使用神经成像技术更好地了解基底神经节网络及其在运动障碍的病理生理学中的作用。我可以在华盛顿大学获得世界一流的设施，众多的教学课程和研讨会，以及博士的出色指导。 Perlmutter，Mach和Schlaggar。获得此奖项将是确保受保护时间和目标努力所需的资源的独特机会。肌张力障碍是一种非自愿运动障碍，其特征是重复性图案或持续的肌肉收缩，导致异常姿势。尽管特定的遗传缺陷可能会导致某些形式的肌张力障碍，但这种残疾疾病可能会折磨25万人，但其病因仍然未知，治疗方案不令人满意。常规的肌张力障碍模型融合了多巴胺能途径中的异常，主要关注D2样受体，但是研究尚未确定哪些多巴胺受体亚型最涉及，这些变化如何影响下游功能途径。因此，使用神经影像学，该应用将通过区分D3和D1样受体是否受到影响，以及异常受体水平是否影响相关脑网络的功能连通性来完善当前模型。肌张力障碍的大多数神经影像学工作都集中在D2样（D2，D3，D4）受体上。然而，PET区分受体亚型的能力取决于放射线的选择性。我们发现，原发性局灶性肌张力障碍中的纹状体尖龙结合降低，但该配体也与5-HT（2A）受体结合。其他研究发现降低了RACLOPRIDE的摄取，对于5-HT（2A）的选择性较低，但对于D2和D3受体的选择性接近相等的选择性。随后，我们没有发现与高度选择性的D2配体NMB（D2相比D3的选择性比D3高200倍）。这些发现表明，D3受体（D3 R）的异常可能会解释这些差异，因此是肌张力障碍的关键多巴胺能异常。此外，确定D1样受体是否也异常也很重要，因为有新的D1和D3受体的协同功能的证据，以及关于D1类受体在肌张力障碍中的作用的现有数据非常有限。最后，内源性多巴胺水平的改变可以解释受体结合异常，需要澄清。多巴胺能途径在介导纹状体的突触可塑性中起着核心作用，而D3 R可以通过自动调节特性，与D1样受体的相互作用以及对纹状体多巴胺水平的调节作用来促进这种作用。因此，纹状体D3 r的扰动可能会扰动导致肌张力障碍的皮质 - thalamo-cerebellar回路的功能。我们将使用静止状态功能连接MRI检查这些功能网络在肌张力障碍中的完整性。我们建议使用新颖的神经影像技术来检验肌张力障碍症中临界多巴胺能异常及其对大脑功能网络的后果的假设。具体而言，我们将确定原发性局灶性障碍症的成年患者是否降低了纹状体D1样结合，纹状体多巴胺减少，纹状体D3结合降低（在验证了使用拟议的D3放射线在非人类灵长类动物中的D3放射线的使用后，以及与区域多巴胺结合杂质相关的功能性网络。这些信息可以转化为新的治疗靶标，这是使用我们的新型D3受体配体和精炼当前的肌张力障碍模型在其他人群中开放新的研究途径。我计划在奖励期结束时使用此提案中收集的经验和数据申请R01。 R01可以包括对多巴胺受体的研究和其他形式的肌张力障碍的功能连通性，以寻找肌张力障碍亚型的病理生理学的共同点或差异。 D2 R，D3 R和D1样受体的选择性配体可用于研究PD中发育不良的病理生理学，因为它们在PD治疗的这种残疾副作用的发展中可能作用。此外，我可以研究肌张力障碍对慢性GPI DBS的缓慢反应是否与多巴胺受体亚型的任何改变有关。从放射性验证的D3 r验证中获得的知识和经验也可以应用于其他放射性物体，也可以研究肌张力障碍。胆碱能系统被认为有助于肌张力障碍的病理生理，而Mach博士实验室正在开发一种配体来标记囊泡乙酰胆碱转运蛋白。我将设计和执行验证研究，并将放射线应用于肌张力障碍。总而言之，我申请这项职业发展赠款的目标是完成上述项目，以获得实质性的研究和临床技能，每年至少发表一篇初始的论文，每年在国家会议上进行研究，并在该指导职业奖的第三年申请R01，以制定自己的独立研究计划。