| 项目编号: | 1452492
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| 项目名称: | CAREER: Development of DNA nanocarriers to redirect immune cells toward chosen targets |
| 作者: | Matthias Stephan
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| 承担单位: | Fred Hutchinson Cancer Research Center
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| 批准年: | 2014
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| 开始日期: | 2015-09-01
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| 结束日期: | 2020-08-31
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| 资助金额: | USD400416
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| 资助来源: | US-NSF
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| 项目类别: | Continuing grant
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| 国家: | US
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| 语种: | 英语
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| 特色学科分类: | Engineering - Chemical, Bioengineering, Environmental, and Transport Systems
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| 英文关键词: | t cell
; diseased cell
; project
; immune cell
; lymphocyte
; receptor targeting
; tumor target
; career opportunity
; vaccine
; targetable pathogen
; dna nanocarrier
; immune system
; erratic cell
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| 英文摘要: | PI: Stephan, Matthias
Proposal Number: 1452492
Medicine currently lacks an intervention that can rapidly educate the immune system to eliminate diseased cell populations, such as those produced by cancer or virus infections. For example, although vaccines can train the immune system to selectively destroy diseased cells without damaging healthy tissue, they may require months to elicit responses, by which time the condition can become lethal. To address this problem, the project proposed here merges concepts from materials science, immunology, and gene therapy to create injectable reagents that can quickly reprogram circulating immune cells to recognize and destroy tumors. Specifically, it tests the hypothesis that targeted, gene-bearing nanoparticles can genetically reprogram circulating T cells to express receptors that recognize tumor targets, so they can rapidly eliminate them. Early results based on laboratory-raised lymphocytes already establish that a novel nanoparticle configuration can efficiently transfer tumor-reactive receptor genes into these cells. The results of the project could be transformative, by creating a basis for developing a repertoire of gene modification systems customized to rapidly generate immunity against any targetable pathogen; using these, treatment of cancer or viral infections could begin immediately following diagnosis by simply applying the appropriate nanoparticle reagents. Also, as an alternative to immunizing populations to protect against uncommon diseases, nanoparticle programming of immune cells could provide this protection "on demand." Thus, the project may impact public health by enabling rapid responses to outbreaks and epidemics. In addition, the investigator's interdisciplinary team of chemists, bioengineers and immunologists will directly integrate this research into a variety of teaching and educational outreach programs to provide K-12 students and their teachers with real-world-based, state-of-the-art learning experiences concerning how developments in biomaterials can impact medicine.
Vaccination evolved into one of the most important therapies of modern medicine, and advances in nanotechnology have provided tools that can amplify immune responses to vaccines. However, even though vaccines can create T cells with defined specificities, they do so slowly and often produce insufficient numbers to control established disease. To date, no methodology is available that can rapidly educate the immune system to destroy diseased cells. This project proposes to develop an injectable synthetic vehicle that can quickly reprogram circulating T cells to recognize and destroy diseased cells. It will test the hypothesis that these lymphocytes can be genetically reconfigured by targeted, gene-bearing nanoparticles to express disease-recognizing receptors, enabling them to bring about rapid rejection of erratic cells. Pilot in vitro studies already establish that efficient transfer of leukemia-reactive T cell receptor (TCR) genes into lymphocytes can be achieved via appropriately engineered nanoparticles. The long-term project goal is to develop a broad repertoire of injectable gene modification systems customized to treat diverse conditions. This goal will be pursued via three specific aims: (1) optimize the design of a nanoscale gene delivery system that achieves persistent and robust transgene expression in proliferating T cells; (2) investigate how internalization of polymeric nanocarrriers affects T cells at the molecular level; and (3) measure how the introduction of specific receptor genes into circulating T cells induces disease regression in mice. DNA encoding a TCR specific for the Wilms tumor antigen will be encapsulated in lipid bilayer-coated porous silica nanoparticles, which will be selectively targeted to circulating T cells by coupling anti-CD3 antibodies onto them. Initial experiments will determine whether stable receptor expression can be achieved in dividing lymphocytes by inserting into the TCR gene a Scaffold/matrix attachment region (S/MAR) sequence, which enables plasmids to self-replicate as episomes. The possibility that nuclear localization signals will increase gene transfer into T cells will also be investigated. Detailed gene expression profiling will clarify how nanoparticle uptake affects lymphocytes at the molecular level. The therapeutic potential of the technology will be tested in leukemia-bearing mice receiving systemic injections of DNA nanocarriers at different doses and frequencies, and the percentage of reprogrammed T cells in the peripheral blood will be quantified by flow cytometry. Differences in tumor progression between treatment groups will be measured using serial bioluminescence tumor imaging. Technologies arising from the project could potentially impact any disease that has a defined antigen for receptor targeting. They are based on a novel scheme that can quickly induce active immunity "on demand", and the therapeutics involved are amenable to rapid distribution, simple storage and easy application. Considering the shortcomings of conventional immunotherapy, this approach could evolve into a new biotechnology arena with broad applications. The research will also be directly integrated into educational programs promoting awareness of career opportunities at the interface of materials science and immunology. |
| 资源类型: | 项目
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| 标识符: | http://119.78.100.158/handle/2HF3EXSE/93310
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| Appears in Collections: | 影响、适应和脆弱性
气候减缓与适应
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| Recommended Citation: | |
Matthias Stephan. CAREER: Development of DNA nanocarriers to redirect immune cells toward chosen targets. 2014-01-01.
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