AROMATIC L-AMINO ACID DECARBOXYLASE MODULATION

描述：（改编自研究者摘要）：超过30 多年来，L-DOPA的管理一直是患者的治疗选择 帕金森病（PD），一种主要发生在老年人身上的疾病。延长 然而，用L-DOPA治疗与破坏性运动波动有关， 以及随着时间的推移而丧失效力。关于为什么有很多讨论 左旋多巴治疗失去了效果，但形成多巴胺（DA）的酶 芳香族L-氨基酸脱羧酶（AAAD），通常被排除在 这场辩论。现在有压倒性的证据表明，AAAD，需要为 多巴胺的生物合成在大脑中受到调节。AAAD活动经历了短暂的- 和长期的变化，在体内，酶的激活和诱导， 涉案酶调节是通过神经递质受体实现的， 第二信使依赖途径。短期激活与 酶的磷酸化。除了理论上的兴趣， AAAD的调节可能对PD中的L-DOPA治疗有影响。 AAAD的药理学增强，AAAD形成的控制步骤 来自外源性L-DOPA的DA可能改善对L-DOPA的临床反应;而， AAAD活性的不受控制的波动可以解释“开-关”现象。 有三个目标：#1。神经递质作用的特点 在AAAD的调制受体; #2。评估老龄化的作用， 多巴胺能损伤对AAAD调节的严重性;和#3。探讨 磷酸化AAAD。这些研究集中在多巴胺能神经元的AAAD， 年轻，成熟和老年小鼠的黑质纹状体神经元，以及小鼠 MPTP损伤。他们扩展了我们在识别神经活性物质类别方面的工作， 增加AAAD活性并具有临床应用潜力的药物 应用程序.除了多巴胺能受体，现在有证据表明， 谷氨酸、烟碱和多巴胺能受体可能参与AAAD的调节。目标1 研究这些神经递质系统及其在AAAD中的可能作用 调节，并评估是否增加AAAD活性导致更多的DA 由左旋多巴形成PD在老年人和老年人中很常见。 随着年龄的增长，更多的多巴胺能神经元退化。目标#2是AAAD的研究， 多巴胺能神经元的老化和退化如何影响 调节酶活性。AAAD的短期调节在一定程度上受到控制， 通过磷酸化。目标#3利用体外靶向、原位、离体和 定点诱变实验，继续我们的努力，以确定 激酶参与，研究磷酸化位点及其 活动的重要性，并探讨如何老化和病变的严重程度 影响AAAD磷酸化。该提案具有直接的临床相关性， PD，因为它解决了酶绝对需要的功能， 左旋多巴治疗成功

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.