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

亨廷顿病中 TrkB 的腺苷 A2A 受体交叉激活

• 批准号: 8104912
• 负责人: DONALD C LO
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104912
• 关键词: Address; Adenosine; Adenosine A2A Receptor; Affect; Agonist; Alleles; Animal Model; Biological Assay; Brain; Brain Part; Brain region; Brain-Derived Neurotrophic Factor; Clinical; Clinical Trials; Complex; Corpus striatum structure; Disease; Disease model; Dopamine D2 Receptor; Drug Delivery Systems; Environment; Evaluation; FDA approved; Foundations; Genes; Glutamine; Goals; Health; Hereditary Disease; Huntington Disease; In Vitro; Intervention; Ligands; Mediating; Modeling; Motor; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome Measure; Palliative Care; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preparation; Property; Proteins; Receptor Signaling; Running; Series; Signal Pathway; Signal Transduction; Slice; Staging; Symptoms; System; Testing; Tetrabenazine; Therapeutic; Therapeutic Uses; Tissues; United States; autocrine; base; disability; drug candidate; gain of function; human Huntingtin protein; in vivo; loss of function; mutant; neurobehavioral; neuroprotection; neuropsychiatry; neurotrophic factor; paracrine; polyglutamine; receptor; research clinical testing; small molecule

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.

描述（由申请人提供）：亨廷顿氏病（HD）是一种主要的遗传疾病，是由亨廷顿蛋白基因（HTT）中聚谷氨酰胺结构域扩张引起的，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功能性能以及对正常HTT等位基因的功能/干扰的潜在丧失。至关重要的是，缺乏临床验证的HD目标是迫切需要识别和理解潜在有益药物靶标的作用机制，并且重要的是，可以证明可以使用具有良好药物样特性的治疗性候选分子来解决此类靶标。目前的提案着重于越来越多地与HD有关的两个此类候选靶标/途径之间的潜在交集：腺苷2A受体（A2AR）和TRKB受体。最近的证据表明，A2AR下游信号传导的重要方面实际上可以通过与TRKB受体的交叉激活方式介导的，而TRKB受体独立于TRKB配体（例如BDNF），在HD病原体中，其正常的皮质提供了对纹状体的正常提供。如果是这样，则这种机制（如果在HD的背景下操作）可能会带来治疗的机会，以使用A2AR配体通过TRKB的交叉激活来提供营养支持以使纹状体神经元退化。此外，如果支持这种机制，则已经可以在HD模型中评估后期临床测试中的BBB - 渗透剂A2AR配体，以用于治疗HD的临床用途。因此，该R21提案的目的是为核心假设提供原则证明，即A2AR调节可以通过TRKB受体的交叉激活在HD的情况下为在HD的情况下为纹状体神经元提供益处。在这些研究中，我们将使用基于大脑切片的HD测定模型，该模型批判性地保留了纹状体和皮层的局部组织环境，以便在体内设置中最大程度地预测体内的体内/EX ex ex Vivo制备。如果支持性，则基于大脑切片的HD测定中的这些发现应为完整的R01应用提供必要的基础，以使用神经病理学以及神经病理学结果指标检查整个HD模型中的这种机制和治疗机会。 公共卫生相关性：亨廷顿氏病（HD）是一种致命的，主要的遗传疾病，是由于亨廷汀基因（HTT）中聚谷氨酰胺结构域的扩展引起的，仅在美国就影响了约35,000人。当前，这种毁灭性疾病尚未知道，可用的姑息治疗仅在治疗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靶标的迫切需要识别和理解潜在有益药物靶标的作用机制，并且重要的是，使用具有良好药物样性质的治疗性候选分子可以证明可以解决此类靶标。本提案将测试靶向腺苷2A受体的现有小分子药物可用于利用“神经营养”或保证健康的途径，即BDNF-TRKB途径，该途径在HD中变得不足并有助于大脑的重要部位，尤其是纹状体。迄今为止，事实证明，在临床试验中，使用BDNF蛋白本身的使用是高度问题的，因此通过替代方式激活其受体TRKB可以通过这种潜在的终点运行，通过该终端可以使用具有更好的药物特性的候选药物来为HD中造成的关键神经营养能力提供对属性的关键神经营养支持。