Enhancement of Phrenic Long-Term Facilitation Following Intermittent Hypoxia

间歇性缺氧后膈长期促进的增强

• 批准号: 7487615
• 负责人: Michael S. Hoffman
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487615
• 关键词: Acute; Adenosine; Adenosine A2A Receptor; Affinity; Amyotrophic Lateral Sclerosis; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Cellular Membrane; Cervical; Data; Development; Doctor of Philosophy; Elements; Goals; Hypoxia; Modeling; Motor; NADPH Oxidase; Neurodegenerative Disorders; Obstructive Sleep Apnea; Patients; Play; Protein Biosynthesis; Protein Serine/Threonine Phosphatase; Protein phosphatase; Purinergic P1 Receptors; Reactive Oxygen Species; Receptor Activation; Receptor Protein-Tyrosine Kinases; Respiratory Insufficiency; Role; Spinal; Spinal cord injury; Superoxides; Synapses; Testing; disorder control; interdisciplinary approach; motor control; novel therapeutics; receptor; respiratory; serotonin receptor

DESCRIPTION (provided by applicant): The fundamental hypothesis guiding this proposal is that adenosine release during acute intermittent hypoxia (AIM) modulates the capacity for plasticity in respiratory motor control. Specifically, we postulate that adenosine 2A receptor activation profoundly modulates a well-established model of AlH-induced respiratory plasticity known as phrenic long-term facilitation (pLTF). Preliminary data have demonstrated that adenosine A2A receptor antagonists greatly enhance pLTF following AIM and that the relevant A2A receptors are located in cervical spinal regions associated with the phrenic motor nucleus. AlH-induced pLTF requires serotonin receptor activation and new protein synthesis, including new synthesis of brain derived neurotrophic factor (BDNF). BDNF activates its high affinity receptor tyrosine kinase, TrkB, subsequently leading to pLTF. Reactive oxygen species (specifically superoxide anions derived from NADPH oxidase) are necessary for pLTF, most likely by inhibition of serine/threonine protein phosphatases, an important inhibitory constraint to pLTF. The major goal during this project period is to test the specific hypothesis that A2A receptors modulate these same cellular/synaptic elements known to play critical roles in the mechanism of pLTF. A detailed understanding of mechanisms whereby A2A receptors modulate respiratory plasticity may guide the development of novel therapeutic approaches to treat patients with severe ventilatory control disorders, such as obstructive sleep apnea and respiratory insufficiency in patients with spinal cord injury or neurodegenerative disease (e.g., ALS). Three specific aims will be pursued using a multidisciplinary approach: Aim 1: To test the hypothesis that spinal A2A receptor antagonists enhance pLTF by modulating cellular mechanisms normally giving rise to pLTF. Aim 2: To test the hypothesis that spinal A2A receptor antagonists enhance pLTF by a mechanism that requires reactive oxygen species formation. Aim 3: To test the hypothesis that spinal A2A receptor antagonists modulate serine-threonine protein phosphatase activity, thereby enhancing pLTF

描述（由申请人提供）：指导该提议的基本假设是，急性间歇性缺氧（AIM）期间腺苷的释放调节呼吸运动控制的可塑性能力。具体来说，我们假设腺苷2A受体激活深刻地调制一个完善的模型，铝诱导的呼吸可塑性被称为膈长期促进（pLTF）。初步数据表明，腺苷A2 A受体拮抗剂大大提高pLTF后AIM和相关的A2 A受体位于与膈运动核相关的颈椎区域。AlH诱导的pLTF需要5-羟色胺受体活化和新的蛋白质合成，包括脑源性神经营养因子（BDNF）的新合成。BDNF激活其高亲和力受体酪氨酸激酶TrkB，随后导致pLTF。活性氧物质（特别是来自NADPH氧化酶的超氧阴离子）是pLTF所必需的，最有可能是通过抑制丝氨酸/苏氨酸蛋白磷酸酶，这是pLTF的重要抑制性约束。本项目期间的主要目标是测试特定假设，即A2 A受体调节已知在pLTF机制中发挥关键作用的相同细胞/突触元件。对A2 A受体调节呼吸可塑性的机制的详细理解可以指导开发新的治疗方法来治疗患有严重呼吸控制障碍的患者，例如患有脊髓损伤或神经退行性疾病（例如，ALS）。将采用多学科方法追求三个具体目标：目标1：检验脊髓A2 A受体拮抗剂通过调节通常产生pLTF的细胞机制来增强pLTF的假设。目的2：验证脊髓A2 A受体拮抗剂通过需要活性氧形成的机制增强pLTF的假设。目的3：验证脊髓A2 A受体拮抗剂调节丝氨酸-苏氨酸蛋白磷酸酶活性，从而增强pLTF的假设