Reconstruction of nigrostriatal pathway by photopolymerized neurotrophin...

描述(申请人提供)：历史上，用于治疗帕金森症的胎儿多巴胺组织移植物被移植到纹状体，纹状体是多巴胺的作用部位，通常从黑质(SN)通过黑质纹状体途径传递。通过胎儿腹侧中脑(VM)组织移植简单地向纹状体补充多巴胺，在治疗帕金森病(PD)方面取得了微乎其微的成功，可能是因为控制多巴胺释放的适当回路尚未建立。替换黑质中丢失的细胞和重建黑质纹状体通路可能会提供持续的长期改善。我们建议在帕金森氏病的啮齿动物模型中验证这一假设，使用VM组织移植到SN中功能正确的位置，然后使用含有神经营养因子微粒(GDNF和BDNF)的可降解聚合物水凝胶。这种聚合物将把SN连接到纹状体，纹状体是通路的末端。聚合物水凝胶的目的是提供一个固体和临时的表面，移植组织长出的轴突可以附着并跟随到纹状体，从而重建调节多巴胺释放的神经回路。神经营养因子，GDNF和BDNF，已经被证明可以提高移植存活和鼓励轴突生长。因为它们将被结合到聚合物中，所以神经营养递送将以特定的地点和时间的方式进行。聚合物是可降解的，因此不会有永久性的外来存在干扰未来的通路功能或影响周围组织。以往的研究表明，生物可降解聚合物与神经组织具有良好的生物相容性。拟议的研究将创建含有神经营养素的微粒的聚合物水凝胶桥。最适合细胞存活和神经生长的神经营养素浓度和组合将首先使用VM外植体在体外确定。然后，将在体内研究最理想的体外组合，将聚合物桥与VM组织一起移植到6-羟基多巴胺大鼠模型中。水凝胶桥重建功能性黑质纹状体通路的能力将取决于行为功能的改善、多巴胺诱导的运动障碍的减少以及通路的神经解剖学存在。这些研究的成功可能会改变神经移植的重点，从神经递质替代疗法转向神经回路重建。虽然我们正在使用帕金森病的动物模型来测试这一假说，但如果成功，它可能会对其他神经退行性疾病产生影响，包括亨廷顿病或中风。

DESCRIPTION (provided by applicant): Historically, fetal dopamine tissue grafts used to treat parkinsonism have been transplanted into the striatum, the site of action for dopamine, which is normally transmitted from the substantia nigra (SN) through the nigrostriatal pathway. Simply resupplying the striatum with dopamine through fetal ventral mesencephalic (VM) tissue transplants has had marginal success in treating Parkinson's disease (PD) possibly because appropriate circuits for the control of dopamine release are not established. Replacing the lost cells in the SN and reconstructing the nigrostriatal pathway may provide consistent long-lasting improvements. We propose to test this hypothesis in a rodent model of PD, using VM tissue transplanted into the SN, the Functionally correct location, followed by a degradable polymer hydrogel containing microparticles of neurotrophins (GDNF and BDNF). This polymer will bridge the SN to the striatum, the terminal end of the pathway. The purpose of the polymer hydrogel is to provide a solid and temporary surface on which neurite outgrowth from the transplanted tissue can attach and follow to the striatum, thus recreating the neural circuitry which regulates dopamine release. The neurotrophins, GDNF and BDNF, have been shown to enhance transplant survival and encourage neurite outgrowth. Because they will be incorporated into the polymer, neurotrophic delivery will be in a site specific and timed manner. The polymer will be degradable, therefore no permanent foreign presence will remain to interfere with future pathway functioning or to affect surrounding tissue. Previous studies indicate that biodegradable polymers have good biocompatibility with neural tissue. The proposed studies will create polymer hydrogel bridges with neurotrophin containing microparticles. The neurotrophin concentrations and combinations which best suit cell survival and neuritic growth first will be determined in vitro using VM explants. Then the most optimal combination in vitro will be studied in vivo as polymer bridges transplanted in conjunction with VM tissue into the 6-hydroxydopamine rat model. The ability of the hydrogel bridges to reconstruct a functional nigrostriatal path will be determined as indicated by improved behavioral function, reduced dopamine-induced dyskinesias, and a neuroanatomical presence of a pathway. The success of these studies may alter the focus of neural transplantation from neurotransmitter replacement therapies to neural circuitry reconstruction. While we are using an animal model of PD to test this hypothesis, if successful, it could have implications for other neurodegenerative disorders, including Huntington's Disease or stroke.