Kynurenic Acid Formation & Function during Development

犬尿酸的形成

• 批准号: 7013464
• 负责人: ROBERT SCHWARCZ
• 金额: $ 20.15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-17 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013464
• 关键词: NMDA receptors; aminoacid transport; astrocytes; brain metabolism; developmental neurobiology; dopamine hydroxylase inhibitor; dopamine receptor; enzyme activity; excitatory aminoacid; glutamate receptor; glutamyltransferase; histochemistry /cytochemistry; human tissue; kynurenate; kynurenine; laboratory rat; mature animal; membrane transport proteins; microdialysis; neuroregulation; neurotoxicology; perinatal; receptor expression; tissue /cell culture; transaminases

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发挥着重要作用。因此，围产期 EAA 功能受损将产生严重后果，其中可能包括智力低下。犬尿酸 (KYNA) 是色氨酸的代谢产物，在生理条件下存在于大脑中，可以作为 EAA 受体的拮抗剂。在内源性大脑浓度下，KYNA 还可阻断 α7 烟碱乙酰胆碱受体，该受体参与突触发生和认知过程。脑 KYNA 水平在妊娠期间非常高，但在出生后立即急剧下降。这一事实、大脑中 KYNA 形成的严格调节以及 KYNA 抵御围产期缺氧影响的能力，引发了 KYNA 是围产期重要神经调节剂的假设。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部位产生有害影响。该项目将研究 KYNA 在两种已知困扰人类的病理状况中可能发挥的作用 发育中的人类大脑，即产前缺氧和儿童低血糖，后者是青少年糖尿病胰岛素治疗的副产品。在动物中，由于谷氨酸能功能过度活跃（兴奋性毒性），缺氧和低血糖都会导致大脑结构和认知发生变化。由于这些损伤也会干扰大脑 KYNA 的合成，因此药物上调大脑 KYNA 水平可能对受伤者有益 正在发育的大脑。在接下来的资助期内，将在不同的发育阶段研究犬尿氨酸转氨酶（KAT）II和III（大脑KYNA的两种主要合成酶），并在小鼠模型中评估它们在控制大脑KYNA中的相对重要性。产前缺氧或产后早期低血糖。然后，已知可增加或减少大脑 KYNA 的药物干预措施将分别用于改善或恶化由这些早期损伤引起的大脑异常。这些研究将被扩展 包括通过基因工程改造缺乏 KAT II 的小鼠。总而言之，这些研究将全面阐述内源性神经调节剂 KYNA 在围产期缺氧和低血糖两种临床相关模型的病理生理学中的作用。此外，计划中的研究将探索专门影响大脑 KYNA 水平的新分子机制，从而可能影响这些疾病的急性和慢性后果。 发育侮辱。