Evaluating cell type-specific non-dopaminergics as a Parkinson's treatment paradigm

帕金森病(PD)是一种衰弱的神经退行性运动障碍，其特征是 多巴胺能细胞。然而，主要的治疗依赖于补充多巴胺(例如左旋多巴)。 一旦这些药物失效，并导致左旋多巴诱发的运动障碍(LID)。这些 不足之处表明，帕金森病不能单靠多巴胺能通路来理解或治疗。在非 多巴胺能机制、突触受体是操作的主要候选对象，无论相关程度如何 到目前为止，实验还没有产生令人满意的结果。这些干预措施受到了细胞缺乏的影响。 特异性--与帕金森病密切相关的纹状体含有不同类型的细胞，具有相反的行为 功能性。不能针对这些细胞类型中的一种来靶向药物已经产生了一个主要的 对帕金森病的认识和治疗存在差距。为了解决这个限制，我们最近开发了DART(药物 受到拴系的严重限制)，这是一种基因编码的药物靶向技术，提供了第一个机会 确定特定受体在特定细胞类型上的行为作用。在本提案中，我们将应用单元格类型- 小鼠PD和LID模型中突触受体的特异性干预。这项工作将提供前所未有的 对PD和LID病理生理学的电路和分子洞察。此外，它还可能提供以下方面的路线图 细胞类型特异性限制作为提高药物疗效的潜在通用范例。

Parkinson’s disease (PD) is a debilitating neurodegenerative movement disorder, characterized by loss of dopaminergic cells. Primary treatments have relied on replenishing dopamine (e.g. levodopa), however, over time these drugs lose efficacy and lead to incapacitating levodopa induced dyskinesias (LID). These shortcomings suggest that PD cannot be understood or treated by dopaminergic pathways alone. Among non- dopaminergic mechanisms, synaptic receptors are prime candidates for manipulation, however relevant experiments have thus far not yielded promising results. These interventions have suffered from a lack of cellular specificity—the striatum, robustly implicated in PD, contains distinct cell types with opposing behavioral functionality. The inability to target pharmacological agents to just one of these cell types has produced a major gap in the understanding and treatment of PD. To address this limitation, we recently developed DART (Drugs Acutely Restricted by Tethering), a genetically encoded drug-targeting technology that offers the first opportunity to establish behavioral roles of a specific receptor on a defined cell type. In this proposal we will apply cell type- specific synaptic receptor interventions in PD and LID in mouse models. This work will provide unprecedented circuit and molecular insights into PD and LID pathophysiology. In addition, it may provide a roadmap for cell type-specific restriction as a potentially general paradigm for increasing drug efficacy.