Gene Therapy in the Senile Brain and Hypophysis

老年大脑和垂体的基因治疗

基本信息

  • 批准号:
    6865647
  • 负责人:
  • 金额:
    $ 10.56万
  • 依托单位:
  • 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:
    2004-03-01 至 2007-02-28
  • 项目状态:
    已结题

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. In this context, the overall goal of the present proposal is to establish a long-term collaboration between the American and Argentine applicants, who share an interest in the potential of gene therapy for the treatment of neurodegenerative diseases. Three specific objectives are proposed: 1) To assess the performance of self-regulating adeno associated viral (AAV) vectors in the brain of old rats. These vectors harbor a reporter gene encoding humanized green fluorescent protein (hGFP) under the control of the tet-off or tet-on promoter system which can be turned off or on, respectively by administration of tetracycline (Tet) or certain Tet derivatives. The above vectors will be stereotaxically injected in the paraventricular, periventricular and arcuate nuclei, all of which contain dopaminergic (DA) neurons of known vulnerability to aging. 2) To assess the therapeutic efficacy of a self-regulating tet-off AAV vector harboring the gene for human glial cell line-derived neurotrophic factor (hGDNF), a potent neuroprotective molecule. The vector will be stereotaxically injected in the arcuate nucleus of 24-month old rats and 6 months later, its ability to prevent the normal age-related loss of hypothalamic tuberoinfundibular DA (TIDA) neurons will be assessed by quantitative immuno-histochemistry for DA neurons and ELISA for hGDNF. Serum PRL levels (an index of TIDA neuron function) will be monitored in the animals throughout the experiment. 3) To construct two self-regulating adenoviral vectors (RAd) harboring suicide genes under the control of the tet-off system. One of the RAds will harbor a hybrid suicide gene coding for a fusion protein between hGFP and HSV1 thymidine kinase (HSV1-TK), which retains fluorescence and HSV1-TK suicide activity. The other RAd will harbor the separate genes for HSV1-TK and hGFP under the control of a bi-directional Tet-off regulatory element. These two vectors, which are expected to be safer than non-regulatable counterparts, will be employed to treat experimental rat prolactinomas. Further to the above specific objectives, contacts with basic and clinical neuroscientists are planned in the US and Argentina in order to assemble a follow up research program focused on senile brain disorders.
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,与年龄有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。在这方面,本提案的总体目标是在美国和阿根廷申请人之间建立长期合作关系,双方都对基因疗法治疗神经退行性疾病的潜力感兴趣。本文提出了三个具体目标:1)评估自我调节腺相关病毒(AAV)载体在老年大鼠脑中的表现。这些载体含有一个报告基因,编码人源化的绿色荧光蛋白(hGFP),该基因在Tet启动子系统的控制下,可以分别通过四环素(Tet)或某些Tet衍生物关闭或打开。上述载体将立体定向注入室旁核、室周核和弓形核,这些核都含有已知易受衰老影响的多巴胺能(DA)神经元。2)评价含人神经胶质细胞系源性神经营养因子(hGDNF)基因的AAV自调节释放载体的治疗效果。将该载体立体定向注射于24月龄大鼠弓形核中,6个月后,通过DA神经元定量免疫组织化学和hGDNF ELISA检测,评估其预防正常年龄相关性下丘脑结节眼底DA (TIDA)神经元丢失的能力。在整个实验过程中,将监测动物血清PRL水平(TIDA神经元功能的指标)。3)在释放系统的控制下构建两个携带自杀基因的自调节腺病毒载体(RAd)。其中一个RAds将包含一个混合自杀基因,该基因编码hGFP和HSV1胸苷激酶(HSV1- tk)之间的融合蛋白,该蛋白保留荧光和HSV1- tk自杀活性。另一个RAd将在双向触发调控元件的控制下携带HSV1-TK和hGFP的独立基因。这两种载体预计比不可调节的载体更安全,将用于治疗实验性大鼠泌乳素瘤。为了进一步实现上述具体目标,计划与美国和阿根廷的基础和临床神经科学家进行接触,以便建立一个以老年脑疾病为重点的后续研究项目。

项目成果

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RODOLFO G GOYA其他文献

RODOLFO G GOYA的其他文献

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{{ truncateString('RODOLFO G GOYA', 18)}}的其他基金

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:
    7848876
  • 财政年份:
    2008
  • 资助金额:
    $ 10.56万
  • 项目类别:
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:
    7668360
  • 财政年份:
    2008
  • 资助金额:
    $ 10.56万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 10.56万
  • 项目类别:
Gene Therapy in the Senile Brain and Hypophysis
老年大脑和垂体的基因治疗
  • 批准号:
    6721031
  • 财政年份:
    2004
  • 资助金额:
    $ 10.56万
  • 项目类别:
Gene Therapy in the Senile Brain and Hypophysis
老年大脑和垂体的基因治疗
  • 批准号:
    7122720
  • 财政年份:
    2004
  • 资助金额:
    $ 10.56万
  • 项目类别:
CHANGES IN TSH-THYROID FUNCTION DURING AGING IN RATS
大鼠衰老过程中 TSH 甲状腺功能的变化
  • 批准号:
    3020617
  • 财政年份:
    1985
  • 资助金额:
    $ 10.56万
  • 项目类别:
THYMUS NEUROENDOCRINE INTERACTIONS DURING AGING
衰老过程中胸腺神经内分泌的相互作用
  • 批准号:
    3954683
  • 财政年份:
  • 资助金额:
    $ 10.56万
  • 项目类别:
THYMUS-NEUROENDOCRINE INTERACTIONS DURING AGING
衰老过程中胸腺-神经内分泌的相互作用
  • 批准号:
    3910948
  • 财政年份:
  • 资助金额:
    $ 10.56万
  • 项目类别:
THYMUS-NEUROENDOCRINE INTERACTIONS DURING AGING
衰老过程中胸腺-神经内分泌的相互作用
  • 批准号:
    3931985
  • 财政年份:
  • 资助金额:
    $ 10.56万
  • 项目类别:

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