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）是一种显性遗传疾病，由亨廷顿基因（htt）中聚谷氨酰胺结构域的扩增引起，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推测功能获得以及正常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的药物靶点的作用机制，更重要的是，需要证明这些靶点可以使用具有良好的药物样特性的治疗候选分子来解决。目前的建议侧重于两种候选靶点/途径之间的潜在交集，这两种靶点/途径越来越多地涉及HD：腺苷2A受体（A2AR）和TrkB受体。最近的证据表明，A2AR下游信号的重要方面实际上可能是通过TrkB受体的交叉激活介导的，这种方式独立于TrkB配体，如BDNF，在HD发病过程中，皮质向纹状体的正常供应受到损害。如果是这样，这种机制，如果在HD的情况下起作用，可能会提供一个治疗机会，使用A2AR配体通过TrkB的交叉激活为退化的纹状体神经元提供营养支持。此外，如果这一机制得到支持，晚期临床试验中的bbb渗透A2AR配体已经可用于HD模型的评估，以用于治疗HD的潜在临床应用。因此，本R21提案的目标是为核心假设提供原理证明，即A2AR调节可以通过交叉激活TrkB受体，为HD背景下发生神经退行性变的纹状体神经元提供益处。在这些研究中，我们将使用基于脑切片的HD分析模型，关键是保留纹状体和皮层的局部组织环境，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。如果支持的话，这些基于脑切片的HD实验的发现应该为完整的R01应用提供必要的基础，通过神经行为和神经病理结果测量来检验这种机制和HD全动物模型的治疗机会。