Targeting CNTF to increase adult forebrain neurogenesis

靶向 CNTF 增加成人前脑神经发生

• 批准号: 7891162
• 负责人: THEO HAGG
• 金额: $ 29.44万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891162
• 关键词: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adult; Adverse effects; Affect; Agonist; Antibodies; Astrocytes; Brain; Cells; Ciliary Neurotrophic Factor; Clinical Trials; Corpus striatum structure; Cyclic AMP; Data; Denervation; Dopamine Agonists; Dopamine D2 Receptor; Dose; Drug Delivery Systems; FDA approved; Failure; Glial Fibrillary Acidic Protein; Human; Injection of therapeutic agent; Intervention; Ischemia; Ischemic Stroke; Lateral; Mediating; Mediator of activation protein; Midbrain structure; Middle Cerebral Artery Occlusion; Modeling; Mus; Neostriatum; Nervous system structure; Neurons; Oral; Pathway interactions; Peripheral Nerves; Pharmaceutical Preparations; Production; Proliferating; Prosencephalon; Quinpirole; Regulation; Replacement Therapy; Rest; Rodent; Schwann Cells; Serotonin; Stroke; Testing; Time; Transplantation; adult neurogenesis; cytokine; injured; nerve stem cell; nerve supply; nervous system disorder; neuroblast; neurogenesis; novel; receptor; relating to nervous system; repaired; research study; subventricular zone; therapy development

DESCRIPTION (provided by applicant): Endogenous neural precursors in the adult brain might be useful in cell replacement therapies for neurological disorders. The development of treatments that would promote neurogenesis would be facilitated by identification of the endogenous regulators. We have shown that endogenous and injected ciliary neurotrophic factor (CNTF) promotes neurogenesis in the adult mouse subventricular zone in the adult mouse forebrain (SVZ). CNTF is produced mainly by astrocytes and Schwann cells, making it a potentially nervous system-selective drug target. We have shown that CNTF expression is regulated by dopaminergic innervation and through D2 dopamine receptors, which are present on GFAP+ SVZ cells and neural progenitors. We will determine which cells express which transmitter receptors, which cells produce CNTF and which ones respond directly to CNTF. The extent to which glial-derived CNTF mediates D2 receptor-induced neurogenesis will be tested by administering D2 agonist while CNTF is blocked. These experiments may identify a regulation mechanism of neurogenesis that is readily amenable to pharmacological intervention with orally active and clinically approved drugs, and does not rely on the presence of neurons that are lost in neurological disorders. The restricted neurogenesis and expression of CNTF in the SVZ and not the striatum may be determined by overlap between dopaminergic and serotonergic projections. Serotonin promotes neurogenesis through 5-HT1a receptors which are also found on SVZ astrocytes. We will determine whether a 5-HT1a receptor agonist also can increase CNTF expression and increases neurogenesis via CNTF. We will determine whether the D2 and 5-HT1a receptors together regulate this neurogenesis through CNTF. If so, it might be possible that a combination of low doses of 5-HT1a and D2 agonists would robustly stimulate neurogenesis in the SVZ, a strategy which ultimately would reduce side effects of regular doses. In addition, we are targeting receptors that would not increase the CNTF production in the peripheral nerves and rest of the body, which otherwise would result in systemic side effects. Finally, this idea will be tested in a focal stroke model, where neuron replacement in the neighboring neostriatum may be beneficial. This study may identify an important convergent neurogenesis-regulating mechanism that can selectively be manipulated with FDA-approved oral drugs.

描述（由申请人提供）：成人脑中的内源性神经前体可能有助于神经系统疾病的细胞替代疗法。通过鉴定内源性调节剂，可以促进促进神经发生的治疗的发展。我们已经表明，内源性和注射睫状神经营养因子（CNTF）促进成年小鼠室室室中的成年小鼠室室（SVZ）的神经发生。 CNTF主要由星形胶质细胞和Schwann细胞产生，使其成为潜在的神经系统选择性药物靶标。我们已经表明，CNTF表达受多巴胺能神经的调节和通过GFAP+ SVZ细胞和神经祖细胞上的D2多巴胺受体调节。我们将确定哪些细胞表达哪些细胞产生CNTF，哪些细胞对CNTF的反应。胶质衍生的CNTF介导D2受体诱导的神经发生的程度将通过在CNTF被阻断时测试D2激动剂。这些实验可能会确定神经发生的调节机制，该机制很容易通过口服活性和临床认可的药物进行药理学干预，并且不依赖于神经系统疾病中丧失的神经元的存在。 CNTF在SVZ而不是纹状体中受到限制的神经发生和表达可以通过多巴胺能和血清素能投射之间的重叠来确定。 5-羟色胺通过5-HT1A受体促进神经发生，这些受体也在SVZ星形胶质细胞上发现。我们将确定5-HT1A受体激动剂是否也可以增加CNTF表达并通过CNTF增加神经发生。我们将确定D2和5-HT1A受体是否通过CNTF一起调节这种神经发生。如果是这样，则可能将低剂量的5-HT1A和D2激动剂的组合结合在一起，可以牢固地刺激SVZ中的神经发生，该策略最终会减少常规剂量的副作用。此外，我们针对的是不会增加周围神经和身体其余部分中CNTF产生的受体，否则会导致全身副作用。最后，这一想法将在局灶性中风模型中进行测试，在焦点模型中，邻近新纹状体中的神经元替代可能是有益的。这项研究可能会确定一种重要的收敛性神经发生调节机制，可以通过FDA批准的口服药物选择性地操纵。