Neuroprotective Gene Therapy in the Brain of Senile Rats

老年大鼠大脑的神经保护基因治疗

• 批准号: 7418722
• 负责人: RODOLFO G GOYA
• 金额: $ 15.6万
• 依托单位: NATIONAL UNIVERSITY OF LA PLATA
• 依托单位国家: 美国
• 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/7418722
• 关键词: Address; Adenovirus Vector; Age; Age-Months; Age-associated memory impairment; Aging; Alzheimer' 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; Facility Construction Funding Category; 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; Numbers; Parkinson Disease; Parkinsonian Disorders; Pathology; Performance; Peripheral; Physiological; Population; Prevention; Prolactin; Protocols documentation; Public Health; 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; Week; Work; adeno-associated viral vector; age related; aging brain; base; brain metabolism; cognitive function; cognitive neuroscience; day; dopaminergic neuron; 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; research and development; research study; restoration; tool; treatment effect; urban area; vector

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（由申请人提供）：阿根廷城市地区老年人口的增长与许多北美和欧洲城市相当。因此，与年龄相关的神经系统疾病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（例如基因疗法）的研究和开发在该国实际上尚未开发出来。在这种情况下，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）的基因在衰老大鼠的大脑中实施神经营养因子基因治疗。 ），两种临床兴趣日益浓厚的神经保护分子。使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神经系统的能力。多巴胺能 (DA) 神经元，基于 NIA 和 FIC 授予 PI 的 R21 资助期间生成的结果。其次，我们希望进一步开展2006年与William Sonntag博士合作开始的探索性研究，该研究涉及IGF-I基因传递对衰老大鼠认知功能的恢复能力。具体来说，我们建议：1）在老年（24个月）雌性大鼠的下丘脑（HPTL）中实施长期GDNF基因治疗，这是一种成熟的与年龄相关的DA神经元功能障碍模型； 2) 确定老年大鼠 HPTL 中联合 GDNF 和 IGF-I 基因治疗是否比单一营养因子基因递送产生更有效的神经保护作用。 3) 评估IGF-I基因治疗对老年（30个月）雌性大鼠黑质DA神经元的神经保护活性。该治疗旨在逆转帕金森病 (PD) 动物模型中黑质 DA 神经元的显着损失。 4) 实施外周（肌内）IGF-I基因治疗，旨在提高老龄大鼠的血清IGF-I水平，这有望改善其海马依赖性认知功能的降低。腺相关载体和腺病毒载体将用于将基因递送到适当的目标区域。治疗对 DA 神经元群的影响将通过形态测量进行评估。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。受益于国外站点的高龄大鼠（自发性 DA 神经元丢失的独特模型）的可用性，拟议的工作将重点关注与年龄相关的神经退行性病理学（PD）以及与年龄相关的认知衰退，因此解决 NIA 感兴趣的两个领域。该项目也是多学科的（该 PAR 鼓励的一个特点），涵盖神经内分泌学、认知神经科学和生物技术领域。公共健康相关性：现代医学提高了预期寿命，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产生破坏性影响。在这种背景下，新的生物技术策略，如基因治疗和有效的神经保护分子，如胶质细胞系衍生的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破坏性病变的有前途的治疗工具。