AROMATIC L-AMINO ACID DECARBOXYLASE MODULATION

芳香族 L-氨基酸脱羧酶调节

• 批准号: 6195386
• 负责人: NORTON H NEFF
• 金额: $ 32.85万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6195386
• 关键词: age difference; aging; aromatic L aminoacid decarboxylase; decarboxylase inhibitor; dopamine; dopamine agonists; dopamine antagonists; enzyme activity; enzyme induction /repression; enzyme mechanism; immunocytochemistry; laboratory mouse; neurotransmitter metabolism; neurotransmitter receptor; neurotransmitters; phosphorylation; serotonin; site directed mutagenesis

DESCRIPTION: (Adapted from the Investigator's Abstract): For more than 30 years, administration of L-DOPA has been the treatment of choice for patients with Parkinson's disease (PD), a disease primarily of the elderly. Prolonged therapy with L-DOPA, however, is associated with disruptive motor fluctuations, and loss of effectiveness with time. There has been much discussion as to why L-DOPA treatment loses effectiveness, but the enzyme that forms dopamine (DA) from L-DOPA, aromatic L-amino acid decarboxylase (AAAD), is often left out of this debate. There is now overwhelming evidence that AAAD, required for the biosynthesis of DA, is regulated in the brain. AAAD activity undergoes short- and long-term changes in vivo, and enzyme activation and induction are involved. Enzyme modulation is achieved via neurotransmitter receptors and second messenger-dependent pathways. Short-term activation is correlated with phosphorylation of the enzyme. In addition to its theoretical interest, regulation of AAAD might have ramifications for L-DOPA treatment in PD. Pharmacological enhancement of AAAD, the controlling step for the formation of DA from exogenous L-DOPA, may improve the clinical response to L-DOPA; while, uncontrolled fluctuation of AAAD activity may explain the "on-off" phenomenon. There are three aims: #1 . To Characterize the Role of Neurotransmitter Receptors in the Modulation of AAAD; #2. To Evaluate the Role of Aging and Severity of Dopaminergic Lesion on AAAD Modulation; and #3. To Investigate the Phosphorylation AAAD. The studies focus on the AAAD of the dopaminergic nigrostriatal neurons of young, mature and old mice, as well as on mice lesioned with MPTP. They expand our work in identifying classes of neuroactive drugs that increase AAAD activity and have the potential for clinical application. In addition to dopaminergic receptors, there is now evidence that glutamate, nicotinic and serotonergic receptors might modulate AAAD. Aim #1 investigates these neurotransmitter systems and their possible role for AAAD modulation, and evaluates whether increasing AAAD activity results in more DA being formed from administered L-DOPA. PD is common in older people and worsens with age as more dopaminergic neurons degenerate. Aim #2 is a study of AAAD and how aging and degeneration of dopaminergic neurons influences the ability to modulate enzyme activity. Short-term modulation of AAAD is, in part, controlled by phosphorylation. Aim #3 utilizing targeted in vitro, in site, ex vivo and site-directed mutagenesis experiments, continues our efforts to identify the kinases involved, investigates the site(s) of phosphorylation and their importance for activity, and explores how aging and severity of the lesion affect AAAD phosphorylation. This proposal has direct clinical relevance for PD, as it addresses the functionality of an enzyme absolutely required for successful L-DOPA therapy.

描述：（改编自研究者摘要）：超过 30 多年来，左旋多巴给药一直是患者的首选治疗方法 帕金森病 (PD)，一种主要发生于老年人的疾病。延长 然而，左旋多巴治疗与破坏性运动波动有关， 并随着时间的推移而失去有效性。关于原因已经有很多讨论 L-DOPA 治疗失去效力，但形成多巴胺 (DA) 的酶 来自 L-DOPA 的芳香族 L-氨基酸脱羧酶 (AAAD) 通常被排除在外 这场辩论。现在有压倒性的证据表明 AAAD 是 DA 的生物合成在大脑中受到调节。 AAAD 活动经历短暂 以及体内的长期变化，以及酶的激活和诱导 涉及。酶的调节是通过神经递质受体实现的 第二信使依赖性途径。短期激活与 酶的磷酸化。除了其理论兴趣之外， AAAD 的调节可能会对 PD 的 L-DOPA 治疗产生影响。 AAAD 的药理增强，是形成的控制步骤 来自外源性L-DOPA的DA，可以改善L-DOPA的临床反应；尽管， AAAD 活性不受控制的波动可以解释“开关”现象。 有三个目标： #1 。表征神经递质的作用 AAAD 调节中的受体； #2.评估衰老的作用和 AAAD 调节多巴胺能损伤的严重程度；和＃3。调查 磷酸化 AAAD。研究重点是多巴胺能的 AAAD 年轻、成熟和年老小鼠以及小鼠的黑质纹状体神经元 MPTP 损伤。他们扩展了我们在识别神经活性类别方面的工作 增加 AAAD 活性并具有临床潜力的药物 应用。除了多巴胺能受体外，现在有证据表明 谷氨酸、烟碱和血清素受体可能调节 AAAD。目标#1 研究这些神经递质系统及其对 AAAD 的可能作用 调节，并评估增加 AAAD 活性是否会导致更多 DA 由施用的左旋多巴形成。 PD 在老年人中很常见并且会恶化 随着年龄的增长，更多的多巴胺能神经元退化。目标 #2 是对 AAAD 的研究 多巴胺能神经元的衰老和退化如何影响 调节酶活性。 AAAD 的短期调节部分受到控制 通过磷酸化。目标 #3 利用体外、现场、离体和体外靶向 定点诱变实验，继续我们的努力来确定 涉及的激酶，研究磷酸化位点及其 活动的重要性，并探讨病变的老化和严重程度 影响 AAAD 磷酸化。该提议具有直接的临床意义 PD，因为它解决了绝对需要的酶的功能 成功的左旋多巴治疗。