Kynurenic Acid Formation & Function during Development

犬尿酸的形成

基本信息

批准号：
7614348
负责人：
ROBERT SCHWARCZ
金额：
$ 21.5万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7614348
关键词：
Acute Address Affect Affinity Agonist Animals Birth Brain Cerebrum Childhood Cholinergic Agents Cholinergic Receptors Chronic Cognitive Complement Complex Condition Development Enzymes Excitatory Amino Acid Antagonists Excitatory Amino Acid Receptors Excitatory Amino Acids Functional disorder Genetically Engineered Mouse Glutamates Glycine Grant Human Hypoglycemia Hypoxia Injury Insulin Insulin-Dependent Diabetes Mellitus Intervention Kynurenic Acid Kynurenine-oxoglutarate aminotransferase Mental Retardation Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Neuromodulator Numbers Perinatal Perinatal Hypoxia Physiological Play Pregnancy Process Production Regulation Relative (related person)Role Site Staging Transcriptional Activation Tryptophan Up-Regulation alpha-bungarotoxin receptor cholinergic clinically relevant cognitive change critical developmental period design excitotoxicity falls improved in vivo injured kynurenine aminotransferase II mind control mouse model neurotransmission novel postnatal prenatal receptor synaptogenesis synthetic enzyme

项目摘要

Excitatory amino acids (EAAs) and their receptors play an important role in brain development. It follows that impaired EAA function during the perinatal period will have grave consequences, possibly including mental retardation. Kynurenic acid (KYNA), a metabolite of tryptophan, is present in the brain under physiological conditions and can function as an antagonist of EAA receptors. At endogenous brain concentrations, KYNA also blocks the alpha7 nicotinic acetylcholine receptor, which is involved in synaptogenesis and cognitive processes. Brain KYNA levels are remarkably high during gestation and fall precipitously immediately after birth. This fact, the tight regulation of KYNA formation in the brain, and the ability of KYNA to protect against the effects of perinatal hypoxia, have given rise to the hypothesis that KYNA is an important neuromodulator during the perinatal period. KYNA dysfunction in the immature brain may therefore have harmful effects on the developing brain and beyond. This project will examine the possible role of KYNA in two pathological conditions known to afflict the developing human brain, i.e. prenatal hypoxia and childhood hypoglycemia, the latter a by-product of insulin treatment in juvenile diabetes. In animals, both hypoxic and hypoglycemic episodes cause structural and cognitive changes in the brain due to overactive glutamatergic function (excitotoxicity). Since these insults also interfere with cerebral KYNA synthesis, pharmacological up-regulation of brain KYNA levels may prove beneficial to the injured developing brain. During the coming grant period, kynurenine aminotransferases (KATs) II and III- the two major synthetic enzymes of brain KYNA - will be studied at different stages of development, and their relative importance in the control of brain KYNA will be assessed in mouse models of prenatal hypoxia or early postnatal hypoglycemia. Pharmacological interventions known to increase or reduce brain KYNA will then be used to improve or worsen, respectively, brain abnormalities caused by these early insults. These studies will be extended to include mice genetically engineered to lack KAT II. Taken together, these studies will comprehensively elaborate the role of an endogenous neuromodulator, KYNA, in the pathophysiology of two clinically relevant models of perinatal hypoxia and hypoglycemia. In addition, the planned studies will explore novel molecular mechanisms that specifically influence brain KYNA levels and thus may affect the acute and chronic consequences of these developmental insults.

兴奋性氨基酸（EAA）及其受体在大脑发育中起重要作用。因此，在围产期期间，EAA功能受损将带来严重的后果，可能包括智力低下。金尿酸（Kyna）是色氨酸的代谢产物，在生理条件下存在于大脑中，并且可以充当EAA受体的拮抗剂。在内源性脑浓度下，Kyna还阻止了参与突触发生和认知过程的α7烟碱乙酰胆碱受体。脑妊娠期间的Kyna水平非常高，出生后立即急剧下降。这一事实是，大脑中的Kyna形成的严格调节以及Kyna防止围产期缺氧作用的能力，已经引起了以下假设：Kyna是围产期中重要的神经调节剂。因此，未成熟大脑中的Kyna功能障碍可能会对发育中的大脑及其他地区产生有害影响。该项目将研究Kyna在已知的两个病理状况中的可能作用发展人脑，即产前缺氧和儿童低血糖，后者是少年糖尿病中胰岛素治疗的副产品。在动物中，由于过度活跃的谷氨酸能功能（兴奋性），低氧和低血糖发作会导致大脑的结构和认知变化。由于这些侮辱还干扰了脑kyna合成，因此脑kyna水平的药理学上调可能对受伤的受伤有益发展大脑。在即将到来的赠款期间，将在发育的不同阶段进行研究，将研究脑kyna的两种主要合成酶，并且它们在脑kyna的控制中的相对重要性将在产前低氧或早期的后早期低氧或大肿后低血糖症的小鼠模型中评估。然后，已知会增加或减少脑kyna的药理干预措施将分别用于改善或恶化，分别由这些早期侮辱引起的脑异常。这些研究将扩展包括基因设计的小鼠缺乏Kat II。综上所述，这些研究将全面阐述内源性神经调节剂Kyna在两种临床相关模型的围产期缺氧和低血糖模型的病理生理学中的作用。此外，计划的研究将探索特异性影响脑kyna水平的新型分子机制，因此可能会影响这些分子机制发展侮辱。