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Neuroprotective Gene Therapy in the Brain of Senile Rats

老年大鼠大脑的神经保护基因治疗

基本信息

批准号：
7848876
负责人：
RODOLFO G GOYA
金额：
$ 16.05万
依托单位：
NATIONAL UNIVERSITY OF LA PLATA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848876
关键词：
Address Adenovirus Vector Age Age-Months Age-associated memory impairment Aging Alzheimer&apos s Disease American Animal Model Animals Area Argentina Award Behavior assessment Behavioral Biotechnology Blood specimen Brain Chronic Cities Clinical Cognition Cognitive Collaborations Continuous Infusion Control Groups Corpus striatum structure Country Deterioration Dopamine Effectiveness Elderly European Female Figs - dietary Functional disorder Gene Delivery Genes Goals Grant Green Fluorescent Proteins Hand Hippocampus (Brain)Hyperprolactinemia Hypothalamic structure Incidence Individual Injection of therapeutic agent Insulin-Like Growth Factor I Intramuscular Laboratories Lead Lesion Life Expectancy Longitudinal Studies Measures Medical Economics Memory Modeling Modern Medicine Monitor Motor Motor Neurons Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroendocrinology Neurons Parkinson Disease Parkinsonian Disorders Pathology Performance Peripheral Physiological Population Prevention Prolactin Protocols documentation Rat-1 Rattus Recombinants Relative (related person)Reporter Genes Reporting Serum Short-Term Memory Site Spinal Structure of nucleus infundibularis hypothalami Substantia nigra structure Synaptic Transmission Tail Testing Therapeutic Tissues Transgenes Transgenic Organisms Translating Veins Work adeno-associated viral vector age related aging brain base brain metabolism cognitive function cognitive neuroscience dopaminergic neuron economic impact experience gene delivery system gene therapy glial cell line derived neurotrophic factor, rat glial cell-line derived neurotrophic factor indexing interest lateral ventricle male multidisciplinary neurogenesis neurological pathology neuron loss neuroprotection neurotrophic factor novel therapeutics prevent public health relevance research and development research study restoration tool treatment effect urban area vector

项目摘要

DESCRIPTION (provided by applicant): The increase of the elderly population in the urban areas of Argentina is comparable to that of many North American and European cities. Consequently, the incidence of age-related neurological pathologies is becoming a problem of significant medical and economic impact for the country. Unfortunately, research and development of novel therapeutic tools for neurodegenerative diseases, like gene therapy, remain virtually undeveloped in the country. In this context, the overall goal of the present proposal is to implement neurotrophic factor gene therapy in the brain of aging rats, using the genes for glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor I (IGF-I), two neuroprotective molecules of growing clinical interest. Using the aging rat as an animal model of age- related decline in motor and cognitive function, we wish, on the one hand, to continue our collaborative studies with Dr. Martha Bohn on the ability of GDNF and IGF-I to rescue dysfunctional central Dopaminergic (DA) neurons, building on the results generated during an R21 grant awarded by the NIA and FIC to the PI. Secondly, we wish to further develop the exploratory studies started in 2006 in collaboration with Dr. William Sonntag, on the restorative ability of IGF-I gene delivery on cognitive function in aging rats. Specifically, we propose: 1) to implement long-term GDNF gene therapy in the hypothalamus (HPTL) of old (24 mo.) female rats, a well-established model of age-related DA neuron dysfunction; 2) To determine whether combined GDNF and IGF-I gene therapy in the HPTL of senile rats results in a more effective neuroprotection than single trophic factor gene delivery. 3) To assess the neuroprotective activity of IGF-I gene therapy on the nigral DA neurons of senile (30 mo.) female rats. The treatment is intended to reverse the marked loss of nigral DA neurons in this animal model of Parkinson's disease (PD). 4) To implement peripheral (intramuscular) IGF-I gene therapy aimed at increasing serum IGF-I levels in aging rats which is expected to lead to an amelioration of their reduced hippocampal-dependent cognitive functions. Adeno associated and adenoviral vectors will be used for gene delivery to the appropriate target areas. The effects of the treatments on DA neuron populations will be assessed morphometrically. Hypothalamic and nigral DA function will be determined by measuring serum prolactin and performing motor tests, respectively. Profiting from the availability of very old rats (a unique model of spontaneous DA neuron loss) at the foreign site, the proposed work will focus on a relevant age-related neurodegenerative pathology (PD) as well as on age-related cognitive decline, thus addressing two areas of interest for the NIA. The project is also multidisciplinary (a feature encouraged by this PAR), encompassing the fields of neuroendocrinology, cognitive neuroscience and biotechnology. PUBLIC HEALTH RELEVANCE: The increase in life expectancy achieved by modern medicine has led to a progressive rise in the incidence of age-related neurodegenerative diseases like Alzheimer's and Parkinson's, with their destructive consequences on cognition and other brain functions. In this context, new biotechnological strategies like gene therapy and potent neuroprotective molecules like glial cell line-derived neurotrophic factor and insulin-like growth factor I, emerge as promising therapeutic tools for the prevention and treatment of these devastating pathologies.

描述(申请人提供)：阿根廷城市地区老年人口的增长与北美和欧洲的许多城市相当。因此，与年龄相关的神经病理的发病率正在成为对该国产生重大医疗和经济影响的问题。不幸的是，针对神经退行性疾病的新型治疗工具的研究和开发，如基因疗法，在这个国家几乎仍然没有开发出来。在此背景下，本提案的总体目标是利用神经胶质细胞源性神经营养因子(GDNF)和胰岛素样生长因子I(IGF-I)这两种日益受到临床关注的神经保护分子的基因，在衰老大鼠的大脑中实施神经营养因子基因治疗。利用衰老大鼠作为与年龄相关的运动和认知功能下降的动物模型，一方面，我们希望继续与Martha Bohn博士合作研究GDNF和IGF-I拯救功能失调的中枢多巴胺(DA)神经元的能力，建立在NIA和FIC授予PI的R21赠款期间产生的结果。其次，我们希望进一步发展2006年开始的探索性研究，与William Sonntag博士合作，研究IGF-I基因治疗对老龄大鼠认知功能的恢复能力。具体地说，我们建议：1)在老年(24个月)的下丘脑(HPTL)实施长期的GDNF基因治疗。2)确定GDNF和IGF-I基因联合治疗老年大鼠HPTL是否比单一营养因子基因治疗更有效的神经保护作用。3)观察IGF-I基因治疗对老年(30mo)黑质DA神经元的神经保护作用。雌性老鼠。该治疗旨在逆转帕金森病(PD)动物模型中黑质DA神经元的显着丢失。4)实施外周(肌肉内)IGF-I基因治疗，旨在提高衰老大鼠血清IGF-I水平，有望改善其海马依赖认知功能的降低。腺相关和腺病毒载体将用于将基因输送到适当的靶区。这些治疗对DA神经元群体的影响将通过形态计量学进行评估。下丘脑和黑质DA功能将分别通过测量血清催乳素和进行运动测试来确定。得益于外国网站提供的非常年长的大鼠(一种独特的自发DA神经元丢失模型)，拟议的工作将专注于相关的年龄相关神经退行性病理(PD)以及与年龄相关的认知下降，从而解决NIA感兴趣的两个领域。该项目也是多学科的(这一特点受到了PAR的鼓励)，涵盖了神经内分泌学、认知神经科学和生物技术领域。与公共健康相关：现代医学延长了预期寿命，导致阿尔茨海默氏症和帕金森氏症等与年龄相关的神经退行性疾病的发病率逐渐上升，对认知和其他大脑功能造成破坏性后果。在这种背景下，新的生物技术策略，如基因治疗和强大的神经保护分子，如胶质细胞源性神经营养因子和胰岛素样生长因子I，成为预防和治疗这些毁灭性疾病的有前途的治疗工具。