Targeting CNTF to increase adult forebrain neurogenesis

靶向 CNTF 增加成人前脑神经发生

• 批准号: 7483182
• 负责人: THEO HAGG
• 金额: $ 29.73万
• 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/7483182
• 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; Failure; Glial Fibrillary Acidic Protein; Human; Injection of therapeutic agent; Intervention; Invasive; Ischemia; Ischemic Stroke; Lateral; Mediating; Mediator of activation protein; Midbrain structure; Middle Cerebral Artery Occlusion; Modeling; Mus; Neostriatum; Nervous system structure; Neurons; Numbers; Oral; Pathway interactions; Peripheral Nerves; Pharmaceutical Preparations; Production; Proliferating; Prosencephalon; Quinpirole; Regulation; Replacement Therapy; Rest; Rodent; Schwann Cells; Serotonin; Stroke; Testing; Thinking; Time; Transplantation; cytokine; injured; nerve stem cell; nerve supply; nervous system disorder; neuroblast; neurogenesis; novel; receptor; relating to nervous system; repaired; research study; 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）：成人大脑中的内源性神经前体可能可用于神经系统疾病的细胞替代疗法。内源性调节因子的鉴定将有助于促进神经发生的治疗方法的开发。我们已经证明，内源性和注射的睫状神经营养因子（CNTF）可促进成年小鼠前脑（SVZ）脑室下区的神经发生。 CNTF主要由星形胶质细胞和雪旺细胞产生，使其成为潜在的神经系统选择性药物靶点。我们已经证明 CNTF 的表达受到多巴胺能神经支配和 D2 多巴胺受体的调节，这些受体存在于 GFAP+ SVZ 细胞和神经祖细胞上。我们将确定哪些细胞表达哪些递质受体、哪些细胞产生 CNTF 以及哪些细胞直接响应 CNTF。神经胶质来源的 CNTF 介导 D2 受体诱导的神经发生的程度将通过在 CNTF 被阻断时施用 D2 激动剂来测试。这些实验可能会确定神经发生的调节机制，该机制很容易接受口服活性药物和临床批准的药物的药理学干预，并且不依赖于神经系统疾病中丢失的神经元的存在。 SVZ 而非纹状体中 CNTF 的受限神经发生和表达可能是由多巴胺能和血清素能投射之间的重叠决定的。血清素通过 5-HT1a 受体促进神经发生，这些受体也存在于 SVZ 星形胶质细胞上。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 受体是否共同通过 CNTF 调节这种神经发生。如果是这样，低剂量的 5-HT1a 和 D2 激动剂的组合可能会强烈刺激 SVZ 的神经发生，这一策略最终将减少常规剂量的副作用。此外，我们的目标受体不会增加周围神经和身体其他部位的 CNTF 产量，否则会导致全身副作用。最后，这个想法将在局灶性中风模型中进行测试，其中邻近新纹状体的神经元替换可能是有益的。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，该机制可以通过 FDA 批准的口服药物选择性地进行操纵。