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：
7536011
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 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7536011
关键词：
Affect Age Animals Brain Brain-Derived Neurotrophic Factor Cells Characteristics Clinical Clinical Trials 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 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 aged 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）：帕金森氏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的移植是抵消帕金森氏病（PD）症状的有效治疗方法。尽管临床和实验证据表明，移植细胞的存活较低，而移植物的加剧是不完整的，但在移植患者中观察到适度的治疗益处。最近，它证明胚胎茎天花板（ESC）可以在培养中转化为多巴胺神经元，当植入具有实验性帕金森氏病的动物时，可以产生类似于胎儿多巴胺神经元植入物的功能恢复程度。由于通过操纵各种生长因子在培养物中产生的多巴胺神经元是在培养物中产生的，因此仍然尚待确定ESC衍生的多巴胺神经元是否具有与正常发展多巴胺能神经元相似的表型。此外，大脑的动态微环境，尤其是神经营养环境，可能会改变移植的ESC的生存，功能，甚至是命运。初步研究的目的将确定ESC衍生的多巴胺神经元是否保留了各种对发展和成熟多巴胺神经元生存和维持至关重要的细胞标记。特别是，研究将集中于鉴定神经营养因子和神经营养因子受体在ESC衍生的多巴胺神经元上，这些神经元通常与正常多巴胺神经元有关。然后，我们将识别并测量宿主大脑内的各种生长因素，这些因素可能影响移植的ESC的命运，并评估这些因素在衰老和/或衰老期间的退化性病变后如何变化。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；条件将使用各种病变模型和基因治疗技术改变，以改变神经营养因子的表达。将研究ESC衍生多巴胺神经元适应性的宿主年龄变量。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Compacted DNA nanoparticle gene transfer of GDNF to the rat striatum enhances the survival of grafted fetal dopamine neurons.

DOI：
10.3727/096368909x12483162196881
发表时间：
2009
期刊：
Cell transplantation
影响因子：
3.3
作者：
Yurek DM;Flectcher AM;Kowalczyk TH;Padegimas L;Cooper MJ
通讯作者：
Cooper MJ

Partial Reconstruction of the Nigrostriatal Circuit along a Preformed Molecular Guidance Pathway.

沿着预先形成的分子引导途径部分重建黑质纹状体回路。

DOI：
10.1016/j.omtm.2019.06.008
发表时间：
2019
期刊：
Molecular therapy. Methods & clinical development
影响因子：
0
作者：
Ghosh,Biswarup;Zhang,Chen;Ziemba,KristineS;Fletcher,AnitaM;Yurek,DavidM;Smith,GeorgeM
通讯作者：
Smith,GeorgeM

Transgene expression in the striatum following intracerebral injections of DNA nanoparticles encoding for human glial cell line-derived neurotrophic factor.

DOI：
10.1016/j.neuroscience.2011.07.072
发表时间：
2011-10-27
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Fletcher, A. M.;Kowalczyk, T. H.;Padegimas, L.;Cooper, M. J.;Yurek, D. M.
通讯作者：
Yurek, D. M.

DNA nanoparticles: detection of long-term transgene activity in brain using bioluminescence imaging.

DOI：
10.2310/7290.2010.00053
发表时间：
2011-10
期刊：
Molecular imaging
影响因子：
2.8
作者：
Yurek DM;Fletcher AM;McShane M;Kowalczyk TH;Padegimas L;Weatherspoon MR;Kaytor MD;Cooper MJ;Ziady AG
通讯作者：
Ziady AG

Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF.

DOI：
10.1016/j.expneurol.2013.09.022
发表时间：
2013-12
期刊：
EXPERIMENTAL NEUROLOGY
影响因子：
5.3
作者：
Zhang, C.;Jin, Y.;Ziemba, K. S.;Fletcher, A. M.;Ghosh, B.;Truit, E.;Yurek, D. M.;Smith, G. M.
通讯作者：
Smith, G. M.