Reconstruction of nigrostriatal pathway by photopolymerized neurotrophin...

光聚合神经营养素重建黑质纹状体通路...

• 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
• 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

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）：从历史上看，用于治疗帕金森氏病的胎儿多巴胺组织移植物已移植到纹状体中，纹状体是多巴胺的作用部位，多巴胺的作用部位通常是从黑质Nigra（SN）通过Nigrostriatal途径传播的。只需通过胎儿腹侧脑脑（VM）组织移植与多巴胺相互补充，在治疗帕金森氏病（PD）方面取得了微不足道的成功，这可能是因为没有确定适当的控制多巴胺释放的电路。替换SN中丢失的细胞并重建骨纹状体途径可能会提供一致的长期改进。我们建议在PD的啮齿动物模型中使用移植到SN的啮齿动物模型中检验该假设，这是功能正确的位置，然后是含有神经营养蛋白（GDNF和BDNF）的可降解聚合物水凝胶。该聚合物将SN桥接到纹状体，即途径的终端。聚合物水凝胶的目的是提供一个固体和临时的表面，从移植组织中的神经突生长可以附着并跟随纹状体，从而重现调节多巴胺释放的神经回路。神经营养蛋白GDNF和BDNF已被证明可增强移植生存并促进神经突生长。由于它们将被掺入聚合物中，因此神经营养的递送将以特定的和定时的方式进行。聚合物将是可降解的，因此，不会持续的外国存在会干扰未来的途径功能或影响周围的组织。先前的研究表明，可生物降解的聚合物在神经组织中具有良好的生物相容性。拟议的研究将与含有微粒神经营养蛋白的聚合物水凝胶桥产生聚合物水凝胶桥。首先将在体外使用VM外植体确定最适合细胞存活和神经生长的神经营养蛋白浓度和组合。然后，当聚合物桥与VM组织一起移植到6-羟基多巴胺大鼠大鼠模型中时，将在体内研究最佳的组合。水凝胶桥重建功能性黑质纹状体路径的能力将被确定，如改善行为功能，减少多巴胺诱导的运动障碍和途径的神经解剖学存在所示。这些研究的成功可能会改变神经移植从神经递质替代疗法到神经回路重建的重点。当我们使用PD的动物模型来检验这一假设时，如果成功，它可能会对其他神经退行性疾病（包括亨廷顿氏病或中风）产生影响。