Reconstruction of nigrostriatal pathway by photopolymerized neurotrophin...

光聚合神经营养素重建黑质纹状体通路...

基本信息

批准号：
7248648
负责人：
KIMBERLY B BJUGSTAD
金额：
$ 32.37万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-19 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7248648
关键词：
Affect Animal Model Animals Apomorphine Behavioral Brain Brain-Derived Neurotrophic Factor Caliber Cell Survival Cell Transplants Cells Characteristics Clinical Trials Collagen Corpus striatum structure Data Development Dopamine Dose Drug Formulations Dyskinetic syndrome Encapsulated Engineering Ethylene Glycols Exhibits Fetal Tissues Fiber Fibrosis Forelimb Future GDNF gene Gel Goals Graft Survival Growth Huntington Disease Hydrogels Hyperactive behavior Immune response Implant In Vitro Injectable Kinetics Lead Left Length Lesion Location Measures Mechanics Methamphetamine Methods Modeling Motor Nerve Neuraxis Neurites Neurodegenerative Disorders Neurotransmitters Numbers Outcome Oxidopamine Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Pattern Peripheral Peripheral Nervous System Polymers Positioning Attribute Property Purpose Rate Rattus Recovery Regulation Replacement Therapy Research Research Personnel Rodent Model Rotation Route Schwann Cells Site Solid Spatial Distribution Staining method Stains Standards of Weights and Measures Stroke Substantia nigra structure Surface Swelling Symptoms Testing Time Tissue Grafts Tissues Transplantation Transplanted tissue Vertebral column astrogliosis base behavior test biodegradable polymer biomaterial compatibility clinical application controlled release design digital ethylene glycol fetal improved in vivo nervous system disorder neural circuit neurite growth neurotrophic factor nigrostriatal pathway novel photopolymerization programs reconstruction reinnervation relating to nervous system repaired scaffold spinal cord repair success

项目摘要

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.

描述（由申请人提供）：历史上，用于治疗帕金森病的胎儿多巴胺组织移植物已被移植到纹状体中，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。简单地通过胎儿腹侧中脑（VM）组织移植向纹状体补充多巴胺在治疗帕金森病（PD）方面取得了有限的成功，这可能是因为尚未建立控制多巴胺释放的适当回路。替换 SN 中丢失的细胞并重建黑质纹状体通路可能会提供持续持久的改善。我们建议在 PD 啮齿动物模型中测试这一假设，将 VM 组织移植到 SN（功能正确的位置），然后使用含有神经营养素（GDNF 和 BDNF）微粒的可降解聚合物水凝胶。这种聚合物将 SN 桥接至纹状体，即该通路的末端。聚合物水凝胶的目的是提供一个坚固的临时表面，移植组织的神经突生长可以附着在纹状体上，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 已被证明可以提高移植存活率并促进神经突生长。因为它们将被掺入聚合物中，所以神经营养递送将以位点特异性和定时的方式进行。该聚合物将是可降解的，因此不会留下永久的异物存在来干扰未来的通路功能或影响周围组织。此前的研究表明，可生物降解聚合物与神经组织具有良好的生物相容性。拟议的研究将与含有神经营养蛋白的微粒建立聚合物水凝胶桥。首先将使用 VM 外植体在体外确定最适合细胞存活和神经炎生长的神经营养蛋白浓度和组合。然后将在体内研究最佳的体外组合，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路径的能力将由行为功能的改善、多巴胺诱导的运动障碍的减少以及路径的神经解剖学存在所表明。这些研究的成功可能会将神经移植的焦点从神经递质替代疗法转移到神经回路重建。虽然我们正在使用帕金森病动物模型来检验这一假设，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。