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）：胶质细胞系源性神经营养因子（GDNF）家族配体（GFL）是四种同源神经元生长因子，调节神经系统的发育和成人神经系统的维持。 GFL 可促进受神经退行性疾病（如帕金森病）影响的多个神经元群体的存活并增强其代谢和表型状态（即营养状态）。 GFL 的这些有效的生存和营养活性导致它们被开发为治疗神经系统疾病和损伤的治疗剂。为此，了解 GFL 在生理条件下的作用机制将有助于设计利用 GFL 的治疗方案。在发育过程中，GDNF 具有长距离功能，例如促进轴突生长和运动神经元的目标依赖性存活。然而，当仅激活位于神经元轴突末端的受体时，GDNF 或其他 GFL 是否能够支持神经元的存活和生长尚不清楚。此外，神经元生长因子维持神经元营养状态的机制尚未明确。神经生长因子 (NGF) 是生长因子神经营养蛋白家族的成员，通过激活 Ret（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 并不通过产生 GFL 来激活 Ret，而是通过 TrkA、NGF 受体和 Ret 之间的串扰机制发挥作用。我的实验室拥有罕见的能力，可以使用区室化培养物对分离的原代神经元轴突和细胞体进行生化和细胞生物学实验，使我们能够掌握这些重要问题。作为描述神经营养因子在发育中和成人神经系统中作用机制的长期目标的一部分，我们提出以下建议：1）检验 GDNF 作为长距离存活和生长促进因子的假设， 2) 检验 GDNF 受体 Ret 在激活后下调决定 GDNF 的局部和长距离信号传导能力的假设，3) 检验 NGF 通过抑制增强 Ret 激活的假设通过调节 Cbl-3 和 CD2AP（受体酪氨酸激酶的两个重要调节因子）实现 Ret 活性依赖性降解。 GDNF 家族配体 (GFL) 目前正在研究用于治疗神经退行性疾病，如帕金森病、亨廷顿病、ALS 和视网膜疾病，以及神经系统损伤，如脊髓损伤 (SCI) 和中风。 Neurturin 是该家族的一员，目前正在进行帕金森病的 II 期临床试验。因此，了解 GFL 的局部和长距离信号传导能力以及了解 GFL 传递生存和生长的分子机制将有助于设计采用 GFL 的治疗策略。