Reconstruction and Regulation of Neural Circuitry by Human Neurons

摘要 细胞疗法有望治愈中枢神经系统疾病。一些帕金森氏症的临床益处表明了这一点 接受人胎儿中脑组织移植替代的疾病(PD)患者 变性的中脑多巴胺(MDA)神经元。高效地产生功能神经元的能力 人类多能干细胞(PSCs)拓展了细胞治疗的前景。然而，对许多人来说，细胞疗法 神经疾病面临着重大障碍。特别是，移植的神经元经常无法重建 专用于丢失功能的功能电路。在帕金森病患者中，DA神经元通常被直接移植到 纹状体，而不是其原发部位的实质黑质。因此，移植的细胞和它们的 修复后的电路失去了用于功能调制的适当输入。 为了解决这些关键问题，我们将通过细胞移植重建黑质-纹状体回路 并确定移植的人丙二醛神经元是否特异性地投射到 纹状体形成功能回路，如果通过调节移植物活性加速重联(目标1)。 此外，我们还将探索通过表达来调节移植细胞修复的神经回路。 HPSCs中DREADD(由设计药物独占激活的设计受体)的活性或抑制形式 从而改善治疗结果(目标2)。从这项研究中获得的信息将是 有助于恢复和调节帕金森病和其他神经疾病的神经回路。

ABSTRACT Cell therapy holds promise for CNS disorders. This is suggested by clinical benefits in some Parkinson's disease (PD) patients who received transplantation of human fetal mesencephalic tissues to replace degenerated midbrain dopamine (mDA) neurons. The ability to produce functional neurons efficiently from human pluripotent stem cells (PSCs) expands the prospect of cell therapy. However, cell therapy for many neurological conditions faces major hurdles. In particular, transplanted neurons often fail to reconstruct a functional circuit that is specific to lost function. In PD, DA neurons are often transplanted directly into the striatum, rather than their home location substantial nigra. Consequently, the grafted cells and their repaired circuit lose appropriate inputs for functional modulation. To address these critical issues, we will reconstruct the nigra-striatal circuit by cell transplantation to the nigra in a PD model mouse and determine if the grafted human mDA neurons project specifically to the striatum to form functional circuit and if the reconnection is sped up by regulating graft activity (Aim 1). Furthermore, we will explore to regulate the neural circuit repaired by transplanted cells by expressing active or inhibitory form of DREADD (designer receptor exclusively activated by designer drug) in hPSCs so that the therapeutic outcomes may be refined (Aim 2). Information gained from this study will be instrumental for restoring and regulating neural circuitry in PD and other neurological conditions.