Trace Amines as Novel Modulators of Spinal Motor Function

微量胺作为脊髓运动功能的新型调节剂

• 批准号: 7329918
• 负责人: ELIZABETH A GOZAL
• 金额: $ 4.1万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329918
• 关键词: Acids; Affect; Age; Air; Amines; Amino Acids; Anabolism; Ankle; Aromatic Amino Acids; Aromatic-L-Amino-Acid Decarboxylases; Automobile Driving; Bathing; Binding; Bioavailable; Biological Models; Blood - brain barrier anatomy; Brain; Carboxy-Lyases; Chest; Chromosome Pairing; Class; DOPA decarboxylase; Diet; Disease; Dopamine; Dose; Enzymes; Epinephrine; Family; Figs - dietary; Fire - disasters; Flexor; G-Protein-Coupled Receptors; Goals; Hindlimb; Hip region structure; In Vitro; Injection of therapeutic agent; Knee; Label; Lead; Locomotion; Mammals; Measures; Metabolic; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Motor; Motor Activity; Motor Neurons; Movement; Muscle; N-Methylaspartate; Names; Neonatal; Nerve; Nervous System Trauma; Neuraxis; Neurons; Neurotransmitters; Norepinephrine; Octopamine; Pathway interactions; Pattern; Pharmacology; Phenethylamines; Phenotype; Phenylalanine; Physiological; Plant Roots; Presynaptic Terminals; Property; Range; Rate; Rattus; Recruitment Activity; Seminal; Serotonin; Side; Signal Pathway; Speed; Spinal; Spinal Cord; Spinal cord injury; Synapses; Synaptic Cleft; System; Testing; Therapeutic; Tryptamines; Tryptophan; Tyramine; Tyrosine; Vesicle; Work; base; day; foot; in vitro Model; in vivo; indexing; interest; intraperitoneal; kinematics; monoamine; neonate; novel; postnatal; postsynaptic; presynaptic; receptor; synthetic enzyme; tryptamine

DESCRIPTION (provided by applicant): The long-term goal is to understand the physiological relevance of the trace amines (TAs) as an intrinsic spinal modulatory system. TAs, named for their low endogenous concentrations in mammals, are related to the classic monoamine transmitters, but have been understudied and cast off as false transmitters. However, there are indicators of their potential importance: their heterogeneous central nervous system distribution, their high turnover rates, and the seminal discovery in 2001 of a new class of receptors preferentially activated by TAs. TAs are synthesized from precursor aromatic amino acids (AAAs) by the enzyme, aromatic-L-amino acid decarboxylase (AADC). We have found that the TAs, trace amine receptor 1, and AADC are found in motoneurons and other neurons in the spinal cord. Moreover, in in vitro studies in the isolated cord, the TAs exert modulatory actions on motor activity including locomotor-like activity. Our work so far only examined motor actions from nerve roots exiting the spinal cord, and provides limited information on motor coordination. We now propose to undertake detailed studies using electromyographic (EMG) recordings from attached hindlimb muscles to test 2 hypotheses. The first hypothesizes that different TAs have distinct actions on motor pool recruitment and locomotor patterning. Using EMG recordings, we will identify the motor pools recruited by the different TAs (i.e. extensors and flexors of hip, knee, ankle, and foot muscles) and analyze their firing properties. The second hypothesis is associated with examining changes in 'dietary' AAAs and TAs on spinal motor function. We hypothesize that alterations in bioavailable levels of TAs intrinsically modulate spinal motor systems. Here, we will use hindlimb EMG recordings as above to study the association between 'circulating' AAA levels and motor activity. Related studies will be undertaken in vivo to examine hindlimb movements produced following systemic injection of AAAs and TAs. Here, motor activity will be assessed by various measures (e.g. onset, duration, movement phenotype) including kinematics. Conclusive evidence that the TAs modulate motor coordination would identify a hitherto unknown intrinsic spinal modulatory system. If their actions are in part controlled by circulating AAAs and TAs, novel diet- based therapies may supplement or supplant existing therapeutic strategies that attempt to facilitate spinal motor function after neurological injuries.

描述（由申请人提供）：长期目标是了解痕量胺（TA）作为内在脊柱调节系统的生理相关性。 TA 因其在哺乳动物中的内源性浓度较低而得名，与经典的单胺递质相关，但尚未得到充分研究并被视为虚假递质。然而，有一些指标表明了它们的潜在重要性：它们的中枢神经系统分布不均匀、周转率高，以及 2001 年开创性地发现了一类新的受体优先被 TA 激活。 TA 由前体芳香族氨基酸 (AAA) 通过芳香族-L-氨基酸脱羧酶 (AADC) 合成。我们发现 TA、微量胺受体 1 和 AADC 存在于脊髓的运动神经元和其他神经元中。此外，在离体脊髓的体外研究中，TA 对运动活动（包括运动样活动）发挥调节作用。到目前为止，我们的工作仅检查了退出脊髓的神经根的运动动作，并提供了关于运动协调的有限信息。我们现在建议使用附着的后肢肌肉的肌电图 (EMG) 记录进行详细研究，以检验 2 个假设。第一个假设是不同的 TA 对运动池招募和运动模式有不同的作用。使用 EMG 记录，我们将识别不同 TA（即髋部、膝部、踝部和足部肌肉的伸肌和屈肌）募集的运动池，并分析它们的发射特性。第二个假设与检查“饮食”AAA 和 TA 对脊髓运动功能的变化有关。我们假设 TA 生物利用度水平的改变本质上调节脊髓运动系统。在这里，我们将使用上述后肢肌电图记录来研究“循环”AAA 水平与运动活动之间的关联。将在体内进行相关研究，以检查全身注射 AAA 和 TA 后产生的后肢运动。在这里，运动活动将通过包括运动学在内的各种措施（例如起始时间、持续时间、运动表型）进行评估。 TA 调节运动协调的确凿证据将鉴定出迄今为止未知的内在脊柱调节系统。如果它们的作用部分受到循环 AAA 和 TA 的控制，那么新的基于饮食的疗法可能会补充或取代试图在神经损伤后促进脊髓运动功能的现有治疗策略。