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细胞可能在神经性疾病的细胞替代疗法中有用。通过识别内源性调节器，将促进促进神经发生的治疗方法的开发。我们已经证明，内源性和注射睫状神经营养因子(CNTF)促进成年小鼠前脑(SVZ)室下区神经发生。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细胞和神经前体细胞上。我们将确定哪些细胞表达哪些递质受体，哪些细胞产生CNTF，哪些细胞直接对CNTF作出反应。神经胶质细胞源性CNTF在多大程度上介导D2受体诱导的神经发生，将通过在CNTF被阻断的情况下给予D2激动剂来测试。这些实验可能确定一种神经发生的调节机制，该机制易于接受口服活性药物和临床批准的药物的药理干预，而不依赖于在神经疾病中丢失的神经元的存在。多巴胺能和5-羟色胺能投射的重叠可能决定了CNTF在SVZ而不是纹状体的表达受到限制。5-羟色胺通过5-HT1a受体促进神经发生，该受体也存在于SVZ星形胶质细胞上。我们将确定5-HT1A受体激动剂是否也能增加CNTF的表达，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共同调节这种神经发生。如果是这样的话，低剂量的5-HT1a和D2激动剂的组合可能会有力地刺激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，在该模型中，邻近新纹状体中的神经元替换可能是有益的。这项研究可能确定一个重要的汇聚性神经发生调节机制，可以选择性地用FDA批准的口服药物来操纵。

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.