AROMATIC L-AMINO ACID DECARBOXYLASE MODULATION

描述：(改编自《调查者摘要》)：超过30年 多年来，L多巴一直是患者的首选治疗方法 帕金森氏病(PD)是一种主要发生在老年人身上的疾病。延长了 然而，L多巴的治疗与颠覆性运动波动有关， 以及随着时间的推移而失去效力。关于为什么会这样，已经有了很多讨论 L-多巴治疗无效，但形成多巴胺(DA)的酶 从L-多巴中，芳香的L-氨基酸脱羧酶(AAAD)往往被遗漏 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活动经历了短暂的- 和体内的长期变化，以及酶的激活和诱导 牵涉其中。酶的调节是通过神经递质受体和 第二信使依赖通路。短期激活与 酶的磷酸化。除了理论上的兴趣之外， AAAD的调节可能对L-多巴治疗帕金森病有影响。 AAAD的药理作用增强是AAAD形成的控制步骤 外源性L多巴的DA可改善L多巴的临床疗效； AAAD活性的不受控制的波动可能解释了“开-关”现象。 有三个目标：#1。为了描述神经递质的作用 受体在调节AAAD中的作用；#2.评估衰老和 多巴胺能损伤对AAAD调节的严重程度；以及#3.研究 磷酸化和脱氧核糖核酸。这些研究主要集中在多巴胺能神经元的AAAD。 幼年、成熟和老年小鼠以及小鼠的黑质纹状体神经元 患上了MPTP。它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 申请。除了多巴胺能受体，现在有证据表明 谷氨酸、尼古丁和5-羟色胺能受体可能调节AAAD。目标1 研究这些神经递质系统及其在AAAD中的可能作用 调制，并评估增加AAAD活性是否会导致更多DA 由L多巴给药而成。帕金森病在老年人中很常见，并会恶化 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和 多巴胺能神经元的老化和退化如何影响 调节酶的活性。AAAD的短期调制在一定程度上是受控制的 通过磷酸化。目的#3利用靶向体外、体内、体外和 定点突变实验，继续我们的努力，以确定 参与的蛋白水解酶，研究了磷酸化的位点(S)及其 对活动的重要性，并探索损伤的老化和严重程度 影响AAAD的磷酸化。这项建议直接与临床相关 PD，因为它解决了一种酶的功能，这种酶是 L-多巴疗法成功。

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.