Adenosine A2A receptor cross-activation of TrkB in Huntington's disease

描述（由申请人提供）：亨廷顿病（HD）是一种显性遗传疾病，由亨廷顿基因（htt）中的多聚谷氨酰胺结构域扩增引起，仅在美国就影响了约35，000人。htt的正常功能在很大程度上仍然未知，疾病机制涉及突变蛋白的假定功能获得以及正常htt等位基因的潜在功能丧失/干扰。至关重要的是，缺乏临床验证的HD靶点迫切需要识别和理解潜在有益药物靶点的作用机制，并且重要的是，需要证明这些靶点可以使用具有良好药物样性质的治疗候选分子来解决。目前的建议集中在两个这样的候选目标/途径之间的潜在交叉点，这些候选目标/途径越来越多地涉及HD：腺苷2A受体（A2 AR）和TrkB受体。最近的证据表明，A2 AR下游信号传导的重要方面实际上可以通过其TrkB受体的交叉激活以独立于TrkB配体（如BDNF）的方式介导，在HD发病过程中，由皮质向纹状体的正常供应受到损害。如果是这样的话，这样的机制，如果在HD的背景下操作，可以提供一个治疗的机会，使用A2 AR配体提供营养支持退化的纹状体神经元通过他们的交叉激活TrkB。此外，如果这种机制得到支持，后期临床测试中的BBB渗透剂A2 AR配体已经可用于HD模型中的评估，以用于治疗HD的临床用途。因此，该R21提案的目标是为核心假设提供原理证明，即A2 AR调节可以通过TrkB受体的交叉激活为HD背景下经历神经变性的纹状体神经元提供益处。对于这些研究，我们将使用基于脑切片的HD测定模型，关键是保留纹状体和皮质的局部组织环境，以便最大限度地预测体内环境，同时提供体外/离体制备的实验途径。如果支持，基于脑切片的HD试验中的这些结果应为R 01的完整应用提供必要的基础，以使用神经行为和神经病理学结局指标在HD的全动物模型中检查该机制和治疗机会。 公共卫生相关性：亨廷顿氏病（HD）是一种致命的显性遗传疾病，由亨廷顿基因（htt）中的多聚谷氨酰胺结构域扩展引起，仅在美国就影响了约35，000人。目前，这种毁灭性的疾病还没有治愈方法，姑息治疗只能部分有效地治疗HD过程中出现的神经精神症状和运动障碍。缺乏临床验证的HD靶点迫切需要鉴定和理解潜在有益药物靶点的作用机制，重要的是，需要证明这些靶点可以使用具有良好药物样性质的治疗候选分子来解决。目前的提案将测试现有的靶向腺苷2A受体的小分子药物可用于进入“神经营养”或健康维持途径BDNF-TrkB途径的命题，该途径在HD中变得缺乏并导致大脑重要部位的退化，特别是纹状体。迄今为止，BDNF蛋白本身的使用已被证明在临床试验中存在很大问题，因此通过替代手段激活其受体TrkB提供了一种潜在的最终运行，通过该最终运行，具有更好的药学特性的候选药物可用于为HD中受损的纹状体提供关键的神经营养支持。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a dominant genetic disorder arising from expansions of the polyglutamine domain in the huntingtin gene (htt), affecting some 35,000 people in the US alone. The normal functions of htt remain largely unknown, with disease mechanism(s) involving presumptive gains-of-function from the mutant protein as well as potential loss of function/interference with the normal htt allele. Critically, the lack of clinically validated targets for HD places an urgent need on identifying and understanding the mechanisms of action of potentially beneficial drug targets, and, importantly, on demonstrating that such targets can be addressed using therapeutic candidate molecules with good, drug-like properties. The present proposal focuses on the potential intersection between two such candidate targets/pathways that have increasingly been implicated in HD: the adenosine 2A receptor (A2AR) and the TrkB receptor. Recent evidence suggests that significant aspects of A2AR downstream signaling may actually be mediated through its cross-activation of the TrkB receptor in a manner that is independent of TrkB ligands such as BDNF, whose normal provision to the striatum by the cortex is compromised during HD pathogenesis. If so, such a mechanism, if operant in the context of HD, could present a therapeutic opportunity to use A2AR ligands to provide trophic support to degenerating striatal neurons via their cross-activation of TrkB. Moreover, if this mechanism is supported, BBB-penetrant A2AR ligands in late-stage clinical testing are already available for evaluation in HD models for potential repurposing for clinical use in treating HD. Thus, the goal of this R21 proposal is to provide proof-of-principle for the core hypothesis that A2AR modulation can provide benefit to striatal neurons undergoing neurodegeneration in the context of HD through cross-activation of the TrkB receptor. For these studies, we will use a brain slice-based assay model for HD that, critically, retains the local tissue environment of the striatum and cortex in order to be maximally predictive for the in vivo setting while providing the experimental access of an in vitro/ex vivo preparation. If supportive, these findings in a brain slice-based HD assay should provide the necessary foundation for a full R01 application to examine this mechanism and therapeutic opportunity in whole-animal models of HD using both neurobehavioral as well as neuropathological outcome measures. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a fatal, dominant genetic disorder arising from expansions of the polyglutamine domain in the huntingtin gene (htt), affecting some 35,000 people in the US alone. Currently, no cures are known for this devastating disease, with palliative treatments available that are only partially effective in treating the neuropsychiatric symptoms and motor disabilities that develop over the course of HD. This lack of clinically validated targets for HD places an urgent need on identifying and understanding the mechanisms of action of potentially beneficial drug targets, and, importantly, on demonstrating that such targets can be addressed using therapeutic candidate molecules with good, drug-like properties. The present proposal will test the proposition that existing small molecule drugs targeting the adenosine 2A receptor could be used to tap into a "neurotrophic" or health-sustaining pathway, the BDNF-TrkB pathway, that becomes deficient in HD and contributes to the degeneration of vital parts of the brain, notably the striatum. To date, the use of the BDNF protein itself has proven to be highly problematic in clinical trials, so activation of its receptor, TrkB, by alternative means provides a potential end run by which drug candidates with much better pharmaceutical properties could be used to supply the critical neurotrophic support to the striatum that is compromised in HD.