Stem Cell Adaptability in Parkinson' Disease

干细胞在帕金森病中的适应性

基本信息

批准号：
7163779
负责人：
David M. Yurek
金额：
$ 30.56万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163779
关键词：
Affect Age Aging Animals Brain Brain-Derived Neurotrophic Factor Cells Characteristics Clinical Clinical Trials Condition Corpus striatum structure DNA Development Dopamine Embryo Environment ErbB4 gene Experimental Parkinsonism Fetus Fiber GDNF gene Glial Growth Factor Graft Survival Growth Factor Implant In Situ Hybridization In Vitro Label Lesion Localized Maintenance Measures Messenger RNA Midbrain structure Modeling Nerve Growth Factor Receptors Neurites Neurons Neurotrophic Tyrosine Kinase Receptor Type 3 Non-Viral Vector Operative Surgical Procedures Parkinson Disease Patients Phenotype Rattus Recombinants Recovery of Function Relative (related person)Research Personnel Site Staging Stem cells Symptoms Techniques Therapeutic Time Transplantation Tyrosine 3-Monooxygenase Viral Vector blastomere structure design dopaminergic neuron embryonic stem cell fetal gene therapy implantation improved in vivo middle age nanoparticle neurotoxic neurotrophic factor nigrostriatal pathway nigrostriatal system receptor reinnervation stem transgene expression young adult

项目摘要

DESCRIPTION (provided by applicant): Stem Cell Adaptibility in Parkinson's Disease Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease (PD). Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. Recently it was demonstrated embryonic stem ceils (ESC) could be converted to dopamine neurons in culture and, when implanted into animals with experimental Parkinson's disease, produced a degree of functional recovery similar to implants of fetal dopamine neurons. Because dopamine neurons derived from ESC are generated in cultures by manipulating various growth factors, it still remains to be determine whether or not ESC-derived dopamine neurons have a similar phenotype as normal developing dopaminergic neurons. Moreover, the dynamic microenvironment of the brain, particularly the neurotrophic environment, may alter the survival, function, and even the fate of transplanted ESC. The objective of the initial studies will determine whether or not ESC-derived dopamine neurons retain various cellular markers that are critical to the survival and maintenance of developing and mature dopamine neurons. In particular, studies will focus on the identification of neurotrophic factors and neurotrophic factor receptors on ESC-derived dopamine neurons that are typically associated with normal dopamine neurons. We will then identify and measure various growth factors within the host brain that may influence the fate of transplanted ESC, and assess how these factors change following a degenerative lesion of the nigrostriatal and/or during aging. Studies will be designed to vary the neurotrophic environment of the host brain in order to determine the adaptability of implanted ESC; conditions will be varied using various lesion models and gene therapy techniques to alter the expression of neurotrophic factors. The variable of host age on ESC-derived dopamine neuron adaptability will be studied.

描述（由申请人提供）：帕金森病的干细胞适应性临床试验提供了令人鼓舞的证据，表明胎儿多巴胺神经元移植是对抗帕金森病 (PD) 症状的有效治疗方法。尽管临床和实验证据表明移植细胞的存活率较低并且移植物神经支配不完全，但在移植患者中观察到了适度的治疗效果。最近，研究表明胚胎干细胞（ESC）可以在培养物中转化为多巴胺神经元，并且当植入患有实验性帕金森病的动物体内时，可以产生与植入胎儿多巴胺神经元类似的一定程度的功能恢复。由于ESC衍生的多巴胺神经元是通过操纵各种生长因子在培养物中产生的，因此ESC衍生的多巴胺神经元是否具有与正常发育的多巴胺能神经元相似的表型仍有待确定。此外，大脑的动态微环境，特别是神经营养环境，可能会改变移植ESC的存活、功能甚至命运。初步研究的目标将确定 ESC 衍生的多巴胺神经元是否保留对发育和成熟多巴胺神经元的生存和维持至关重要的各种细胞标记。特别是，研究将集中于鉴定 ESC 衍生的多巴胺神经元上的神经营养因子和神经营养因子受体，这些神经营养因子通常与正常多巴胺神经元相关。然后，我们将识别和测量宿主大脑内可能影响移植ESC命运的各种生长因子，并评估这些因子在黑质纹状体退行性病变后和/或衰老过程中如何变化。研究将旨在改变宿主大脑的神经营养环境，以确定植入的ESC的适应性；使用各种病变模型和基因治疗技术来改变神经营养因子的表达，从而改变病情。将研究宿主年龄变量对ESC衍生的多巴胺神经元适应性的影响。