Survival and growth-promotion mechanisms of the GDNF family ligands (GFLs)

GDNF 家族配体 (GFL) 的存活和生长促进机制

• 批准号: 7937157
• 负责人: Brian Anthony Pierchala
• 金额: $ 2.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937157
• 关键词: Adaptor Signaling Protein; Adult; Affect; Afferent Neurons; Amyotrophic Lateral Sclerosis; Atrophic; Axon; Back; Biochemical; Biological; Cells; Cessation of life; Degradation Pathway; Development; Disease; Distal; Down-Regulation; Family; Family member; Foundations; GDNF gene; GDNF receptors; Goals; Growth; Growth Factor; Half-Life; Huntington Disease; In Vitro; Laboratories; Ligands; Ligation; Literature; Maintenance; Metabolic; Metabolism; Molecular; Motor; Motor Neurons; NGFR Protein; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous System Trauma; Nervous system structure; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathway interactions; Phase II Clinical Trials; Physiological; Population; Presynaptic Terminals; Production; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Retinal Diseases; Sensory; Signal Pathway; Signal Transduction; Spinal cord injury; Stroke; System; Testing; Therapeutic Agents; Treatment Protocols; axon growth; axon guidance; base; design; glial cell-line derived neurotrophic factor; grasp; in vivo; member; multicatalytic endopeptidase complex; nervous system development; neuronal cell body; neuronal growth; neuronal survival; neurotrophic factor; neurturin; receptor; research study; retrograde transport; sciatic nerve; therapy design; treatment strategy; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are four homologous neuronal growth factors that regulate the development of the nervous system and the maintenance of the adult nervous system. GFLs promote the survival and enhance the metabolic and phenotypic status, i.e. trophic status, of several populations of neurons that are affected in neurodegenerative diseases such as Parkinson's disease. These potent survival and trophic activities of the GFLs has led to their development as therapeutic agents for the treatment of diseases and injuries of the nervous system. To this end, an understanding of the mechanisms of action of the GFLs under physiologic conditions will aid in the design of treatment regimens that utilize the GFLs. During development, GDNF has long-distance functions, such as the promotion of axon growth and target-dependent survival of motor neurons. However, whether GDNF, or other GFLs, are capable of supporting the survival and growth of neurons when only activating receptors located on their axon terminals is unclear. Furthermore, the mechanisms by which neuronal growth factors maintain the trophic status of neurons are not well established. Nerve growth factor (NGF), a member of the neurotrophin family of growth factors, regulates the trophic status of sympathetic neurons via activation of Ret, the heterologous receptor tyrosine kinase for the GFLs. Remarkably, NGF does not activate Ret through the production of GFLs, and instead NGF acts via a cross-talk mechanism between TrkA, the NGF receptor, and Ret. My laboratory has the rare ability to conduct biochemical and cell biological experiments on isolated axons and cell bodies of primary neurons using compartmentalized cultures, bringing these important questions within our grasp. As part of our long-term goal of delineating the mechanisms of action of neurotrophic factors in the developing and adult nervous system we propose the following: 1) to test the hypothesis that GDNF acts as a long-distance survival and growth-promoting factor, 2) to test the hypothesis that the down regulation of the GDNF receptor, Ret, upon activation dictates the local and long-distance signaling capabilities of GDNF, 3) to test the hypothesis that NGF augments Ret activation via the inhibition of the activity-dependent degradation of Ret through the modulation of Cbl-3 and CD2AP, two important regulators of receptor tyrosine kinases. The GDNF family ligands (GFLs) are currently being investigated for the treatment of neurodegenerative diseases such as Parkinson's disease, Huntington's disease, ALS, and retinal diseases, and for injuries of the nervous system such as spinal cord injury (SCI) and stroke. Neurturin, a member of this family, is currently in phase II clinical trials for Parkinson's disease. Therefore, an understanding of the local and long-distance signaling capacities of the GFLs and an understanding of the molecular mechanisms by which GFLs convey survival and growth will aid in the design of treatment strategies that employ GFLs.

描述（由申请人提供）：神经胶质细胞系的神经营养因子（GDNF）家族配体（GFL）是四个同源神经元生长因子，可调节神经系统的发展和成人神经系统的维持。 GFL促进了生存率，并增强了几种神经元种群的代谢和表型状态，即营养状态，这些神经元受到神经退行性疾病（例如帕金森氏病）的影响。 GFL的这些有效的生存和营养活性导致它们成为治疗神经系统疾病和伤害的治疗剂的发展。为此，了解在生理条件下GFL的作用机理的理解将有助于设计利用GFL的治疗方案。在开发过程中，GDNF具有长距离功能，例如促进轴突生长和运动神经元的靶依赖性存活。但是，无论是GDNF还是其他GFL，仅当仅激活位于轴突末端上的受体的受体时，才能够支持神经元的生存和生长。此外，神经元生长因子保持神经元的营养状态的机制尚未得到充分确定。神经营养因子家族的成员神经生长因子（NGF）通过激活RET激活（GFL的异源受体酪氨酸激酶）来调节交感神经元的营养状态。值得注意的是，NGF不会通过GFL的产生激活RET，而是NGF通过TRKA，NGF受体和RET之间的串扰机理起作用。我的实验室具有罕见的能力，可以使用分室化培养物对原代神经元的孤立轴突和细胞体进行生化和细胞生物学实验，从而将这些重要问题带入我们的掌握范围内。作为我们在发展中和成人神经系统中描述神经营养因素作用机制的长期目标的一部分，我们提出以下提议：1）测试GDNF作为长距离存活和增长因素的假说，2）测试以下假说，即在GDNF受体下降低了GDNF受体的信号，并保留了GDNF受体的态度，并保持了激活的态度，并且是激活的态度。 3）检验以下假设：NGF通过通过调节CBL-3和CD2AP（受体酪氨酸激酶的两个重要调节剂）的调节来抑制RET的活性依赖性降解。目前正在研究GDNF家族配体（GFL），以治疗神经退行性疾病，例如帕金森氏病，亨廷顿氏病，ALS和视网膜疾病，以及神经系统的损伤，例如脊髓损伤（SCI）和中风。该家族的成员Neurturin目前正在帕金森氏病的II期临床试验中。因此，了解GFL的局部和长距离信号传导能力以及对GFL传达生存和生长的分子机制的理解将有助于设计采用GFL的治疗策略。