"Enhancement of Brain Tumor Immunotherapy by Fas-L RNAi"
“Fas-L RNAi 增强脑肿瘤免疫治疗”
基本信息
- 批准号:6861161
- 负责人:
- 金额:$ 16.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-05-01 至 2007-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Each year, approximately 185,000 people in the United States are diagnosed with a primary or metastatic brain tumor constituting the third leading cause of death in young adults ages 20-39. Among brain tumors, malignant gliomas are the most common and aggressive malignancies. Gliomas seem to be capable of inducing T-cell apoptosis through the Fas/Fas-ligand (Fas-L) pathway. This mechanism allows them to circumvent immune surveillance by decreasing cell mediated immunity. Brain tumor therapy using immune modulators such as interleukins (IL) increases the recruitment of active T lymphocyte populations and has proven to be an effective strategy in experimental models of the disease. However, due to tumor-secreted Fas-L, the peritumoral T-cells recruited by IL are activated through the trans-membrane Fas receptor, which initiates the caspase-3 mediated apoptotic cascade. Using RNA interference (RNAi) techniques, mRNA from tumor-derived Fas-L could be silenced and T cell apoptosis could be decreased, thus improving antitumor responses and potentiating the effect of interleukin therapy. RNAi sequences can be delivered by retroviruses, guaranteeing a constitutive transfection. In this proposal, the effect that treatment with Fas-L RNAi sequences delivered via retroviruses has on experimental gliomas will be investigated. The effect of this treatment modality will be studied alone and in combination with locally delivered IL incorporated into injectable microspheres. Treatment with Fas-L RNAi sequences is expected to decrease levels of tumor-derived Fas-L, therefore decreasing the rates of T cell apoptosis and increasing the populations of peritumoral T cells. Such an effect should allow a more consistent cell-mediated anti-tumor response able to prolong survival in animal models. Furthermore, the efficacy of locally delivered IL microspheres should be enhanced. The potential benefit of Fas-L RNAi delivered in this fashion could be applicable to several malignancies that have the Fas/Fas-L pathway among their immune privilege strategies.
描述(由申请人提供):每年,美国约有185,000人被诊断患有原发性或转移性脑肿瘤,构成20-39岁年轻人死亡的第三大原因。在脑肿瘤中,恶性胶质瘤是最常见和最具侵袭性的恶性肿瘤。胶质瘤似乎能够通过Fas/Fas配体(Fas-L)途径诱导T细胞凋亡。这种机制使它们能够通过降低细胞介导的免疫来规避免疫监视。使用免疫调节剂如白细胞介素(IL)的脑肿瘤治疗增加了活性T淋巴细胞群体的募集,并且已被证明是该疾病的实验模型中的有效策略。然而,由于肿瘤分泌的Fas-L,由IL募集的肿瘤周围T细胞通过跨膜Fas受体被激活,其启动胱天蛋白酶-3介导的凋亡级联。利用RNA干扰(RNAi)技术,可以沉默肿瘤源性Fas L的mRNA,减少T细胞凋亡,从而提高抗肿瘤疗效,增强白细胞介素治疗的效果。RNAi序列可以通过逆转录病毒递送,保证组成型转染。在这项提议中,将研究通过逆转录病毒递送的Fas-L RNAi序列对实验性胶质瘤的治疗效果。将单独研究这种治疗方式的效果,并与掺入可注射微球中的局部递送IL联合研究。预期用Fas-L RNAi序列治疗会降低肿瘤来源的Fas-L水平,因此降低T细胞凋亡率并增加肿瘤周围T细胞的群体。这样的效果应该允许更一致的细胞介导的抗肿瘤反应,能够延长动物模型中的存活。此外,局部递送的IL微球的功效应当增强。以这种方式递送的Fas-L RNAi的潜在益处可适用于在其免疫豁免策略中具有Fas/Fas-L途径的几种恶性肿瘤。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alessandro Olivi其他文献
Alessandro Olivi的其他文献
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{{ truncateString('Alessandro Olivi', 18)}}的其他基金
"Enhancement of Brain Tumor Immunotherapy by Fas-L RNAi"
“Fas-L RNAi 增强脑肿瘤免疫治疗”
- 批准号:
7617876 - 财政年份:2008
- 资助金额:
$ 16.28万 - 项目类别:
"Enhancement of Brain Tumor Immunotherapy by Fas-L RNAi"
“Fas-L RNAi 增强脑肿瘤免疫治疗”
- 批准号:
7616934 - 财政年份:2008
- 资助金额:
$ 16.28万 - 项目类别:
"Enhancement of Brain Tumor Immunotherapy by Fas-L RNAi"
“Fas-L RNAi 增强脑肿瘤免疫治疗”
- 批准号:
7035873 - 财政年份:2005
- 资助金额:
$ 16.28万 - 项目类别:
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