Targeting CNTF to increase adult forebrain neurogenesis

描述（由申请人提供）：成人大脑中的内源性神经前体可能适用于神经系统疾病的细胞替代疗法。通过鉴定内源性调节剂，将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）促进成年小鼠脑室下区在成年小鼠前脑（SVZ）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。我们已经表明，CNTF的表达是由多巴胺能神经支配，并通过D2多巴胺受体，这是目前的GFAP+ SVZ细胞和神经祖细胞。我们将确定哪些细胞表达哪些递质受体，哪些细胞产生CNTF，哪些细胞直接对CNTF产生反应。将通过在CNTF被阻断的同时施用D2激动剂来测试胶质源性CNTF介导D2受体诱导的神经发生的程度。这些实验可以确定一种神经发生的调节机制，这种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。限制性的神经发生和CNTF在SVZ而不是纹状体的表达可能是由多巴胺能和多巴胺能投射之间的重叠决定的。5-羟色胺通过5-HT 1a受体促进神经发生，5-HT 1a受体也存在于SVZ星形胶质细胞上。我们将确定5-HT 1a受体激动剂是否也能增加CNTF表达并通过CNTF增加神经发生。我们将确定D2和5-HT 1a受体是否通过CNTF共同调节这种神经发生。如果是这样的话，低剂量的5-HT 1a和D2激动剂的组合可能会强烈刺激SVZ中的神经发生，这是一种最终减少常规剂量副作用的策略。此外，我们针对的受体不会增加周围神经和身体其他部位的CNTF产生，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，其中相邻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个重要的会聚神经发生调节机制，可以选择性地与FDA批准的口服药物操纵。

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.