Trophic Factor Signaling and Motor Neuron Death

营养因子信号传导和运动神经元死亡

• 批准号: 7179247
• 负责人: Robert G Kalb
• 金额: $ 28.84万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179247
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenosine A2A Receptor; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Basic Science; Biochemical; Brain; Brain-Derived Neurotrophic Factor; Categories; Cessation of life; Class; Control Groups; Cultured Cells; Degenerative Disorder; Development; Dose; Drug Delivery Systems; Embryo; Event; Family; Functional disorder; Future; Gene Expression; Genes; Glutamate Receptor; Glutamates; Growth Factor; Human; In Vitro; Individual; Inositol; Investigation; K 252a; Lipids; Motor Neuron Disease; Motor Neurons; Mutation; Nerve Growth Factors; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Other Therapy; PDPK1 gene; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Predisposition; Process; Protein Tyrosine Kinase; Publishing; Purinergic P1 Receptors; Randomized; Recombinants; Rodent; Role; Serine; Signal Pathway; Signal Transduction; Specificity; Spinal Cord; Superoxide Dismutase; Tissues; Toxic effect; Translating; Tyrosine Kinase Inhibitor; Work; base; day; enprofylline; excitotoxicity; in vivo; inhibitor/antagonist; inorganic phosphate; killings; motor neuron degeneration; mutant; neurotransmission; novel; prevent; receptor; tissue culture

DESCRIPTION (provided by applicant): The central pathologic event in Amyotrophic Lateral Sclerosis (ALS) is the selective degeneration of motor neurons. While most cases (-90%) are sporadic, the familial cases are due to mutations in a variety of different genes such as SOD1 and p150glued. Excessive activation of glutamate receptors (excitotoxicity) is an early triggering event. The death of motor neurons from excitotoxic insult or mutant gene expression can be studied in cell culture using dissociated rodent embryonic spinal cord tissue. Our previous in vitro work demonstrates that excitotoxic motor neuron death only occurs if Brain-derived neuronotrophic factor (BDNF) signaling via TrkB is intact. The phosphatidylinositol 3' kinase (PI3'K) signaling cascade is activated by TrkB and PI3'K signaling is necessary and sufficient for BDNF-induced excitotoxic death of motor neuron. Pharmacological manipulations that inhibit Trk activation can also protect motor neurons from the toxic effects of mutant SOD1 and p150glued. This can be accomplished using proprietary derivatives of K252a (made by Cephalon Pharmaceuticals) or by inhibiting the activation of adenosine A2A receptors. In specific aim #1 we will examine the alterations in intracellular signaling cascades that follow from administration of these agents. The potential interplay between mutant SOD1 and p150glued and Trk signaling events will also be studied. In specific aim #2, we will study the in vivo pharmacodynamics of these agents on Trk activation and signaling. This is a prelude to future studies in which we hope to examine the efficacy of these agents in animal models of ALS. In specific aim #3 we will study the signaling cascades downstream of activated PIS'K (two serine-theonine kinases (PDK1, Akt) and small monomeric GTP'ases of the RhoA and Arf families) to see which is needed to evoke excitotoxic sensitivity of motor neurons. This will define susceptibility-to-toxicity intracellular signaling pathways in motor neurons. Relevance: The proposed work attempts to translate basic science observations into new treatments for ALS. The development of new drug targets for ALS could guide the way for novel therapies for other, more prevalent, neuro-degenerative disorders.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）的中心病理事件是运动神经元的选择性变性。虽然大多数病例（-90%）是散发性的，但家族性病例是由于多种不同基因（例如SOD 1和p150 glued）的突变造成的。谷氨酸受体的过度激活（兴奋性毒性）是一种早期触发事件。运动神经元由于兴奋性毒性损伤或突变基因表达的死亡可以在使用分离的啮齿动物胚胎脊髓组织的细胞培养物中研究。我们以前的体外研究表明，只有当脑源性神经营养因子（BDNF）通过TrkB的信号转导完整时，才会发生兴奋性毒性运动神经元死亡。TrkB激活磷脂酰肌醇3'激酶（PI 3' K）信号通路，PI 3 'K信号通路是BDNF诱导运动神经元兴奋性毒性死亡的必要和充分条件。抑制Trk激活的药理学操作也可以保护运动神经元免受突变体SOD 1和p150 glued的毒性作用。这可以通过使用K252 a的专有衍生物（由Cephalon Pharmaceuticals制造）或通过抑制腺苷A2 A受体的活化来实现。在具体目标#1中，我们将检查给予这些药物后细胞内信号级联的变化。还将研究突变体SOD 1和p150 glued与Trk信号传导事件之间的潜在相互作用。在具体目标#2中，我们将研究这些药剂对Trk活化和信号传导的体内药效学。这是未来研究的前奏，我们希望在ALS动物模型中检查这些药物的疗效。在具体目标#3中，我们将研究激活的PIS 'K（两种丝氨酸-茶氨酸激酶（PDK 1、Akt）以及RhoA和Arf家族的小单体GTP'酶）下游的信号级联，以了解哪一个是唤起运动神经元兴奋性毒性敏感性所需的。这将定义运动神经元中的易感性-毒性细胞内信号传导途径。相关性：拟议的工作试图将基础科学观察转化为ALS的新治疗方法。ALS新药靶点的开发可以为其他更普遍的神经退行性疾病的新疗法提供指导。