Heritable immunization of the white-footed mouse reservoir of Lyme disease
白足小鼠莱姆病储库的遗传免疫
基本信息
- 批准号:10677804
- 负责人:
- 金额:$ 88.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAlbuminsAllelesAnimalsAntibodiesAreaB-LymphocytesBackBindingBorrelia burgdorferiCell LineChromosomal translocationCommunitiesDeerDisadvantagedDiseaseDisease ReservoirsES Cell LineElementsEngineeringEnterobacteria phage P1 Cre recombinaseEnvironmentEpitopesFeedbackGene Transfer TechniquesGenesGeographyGoalsHeritabilityImmunityImmunizationImmunizeIn VitroIncidenceIndividualInterventionInvestmentsLightLinkLiverLyme DiseaseMethodsMidwestern United StatesMusMutationOspA proteinPlayPopulationPreventionPrevention strategyProductionProtective ClothingReciprocal TranslocationRecombinantsResearch PersonnelResistanceRiskRoleSortingSystemTestingTick-Borne DiseasesTicksTimeTransgenesTransgenic OrganismsVaccinatedWhite-Footed MouseWorkZoonosesacaricidecostdisease transmissionembryonic stem cellexposed human populationfield studyfitnessin vitro activityin vivointerestmodel organismpathogenpreventresistance genetransmission processunderdominance
项目摘要
Project Summary RFA-AI-19-037
The rising incidence of Lyme disease demands new strategies for prevention. Existing methods
such as acaricides, deer reduction, landscaping, and personal protective clothing, are inherently
short-term and must be regularly re-applied, maintained and worn. The Mice Against Ticks
project seeks to develop a durable one-time intervention to disrupt the ecological
cycle of Lyme disease transmission for many decades. The causative agent of Lyme
disease B. burgdorferi is passed back and forth between ticks and their small animal hosts,
which serve as zoonotic reservoirs of disease. The white-footed mouse P. leucopus is widely
considered to be the most important reservoir because it is both ubiquitous and extremely
efficient at acquiring and transmitting pathogens via ticks. Our overarching goal for this
proposed project is to heritably immunize white-footed mice against Lyme by encoding
protective P. leucopus antibodies targeting B. burgdorferi outer surface protein A (OspA) in the
mouse germline. According to our calculations, combining at least four such antibodies should
prevent evolutionary escape by B. burgdorferi because too many simultaneous OspA mutations
would be needed. Crucially, even if these mice are less important in some areas than currently
thought, immunization will reduce the number of infected ticks, which in turn will infect fewer
secondary reservoirs, which will infect fewer ticks, reinforcing a negative feedback spiral
anticipated to greatly reduce the local burden of Lyme disease. We have already successfully
isolated anti-OspA antibodies from OspA-immunized P. leucopus, derived putative P. leucopus
embryonic stem cells, and shown that the albumin locus appears suitable for antibody secretion
from the liver. We now seek to (1) identify antibodies that bind to at least four different OspA
epitopes, (2) establish a stable embryonic stem cell line and perform germline editing, and (3)
generate heritably resistant mice that express antibodies from a cisgenic cassette linked to a
reciprocal chromosomal translocation, a naturally occurring form of high-threshold gene drive
that would enable the reversible and tightly localized engineering of wild P. leucopus
populations. Our open and community-guided approach has met with apparent enthusiasm by
residents of Nantucket and Martha’s Vineyard, indicating that local communities suffering from
tick-borne disease throughout the Northeast and Upper Midwest may wish to immunize their
own wild mouse populations in order to help prevent Lyme disease for many decades.
项目摘要 RFA-AI-19 - 037
莱姆病发病率的上升需要新的预防策略。现有方法
例如杀螨剂、减少鹿、美化环境和个人防护服,
必须定期重新使用、维护和佩戴。 老鼠对蜱虫
该项目旨在开发一种持久的一次性干预措施,以破坏生态环境,
莱姆病的传播周期长达数十年。莱姆病的病原体
疾病B。burgdorferi在蜱和它们的小动物宿主之间来回传播,
它们是人畜共患病的宿主。白足鼠P. leucopus广泛
被认为是最重要的水库,因为它既无处不在,
能够有效地通过蜱虫获取和传播病原体。我们的首要目标是
一个被提议的项目是通过编码一种基因,
保护性P 靶向B的白蛋白抗体。Burgdorferi外表面蛋白A(OspA)
小鼠生殖系根据我们的计算,结合至少四种这样的抗体应该
阻止了B的进化逃逸。burgdorferi因为太多的同时OspA突变
会被需要。至关重要的是,即使这些小鼠在某些领域的重要性不如目前
我认为,免疫接种会减少受感染的蜱虫数量,从而减少感染
次级储库,这将感染更少的蜱虫,加强负反馈螺旋
预计将大大减轻当地莱姆病的负担。我们已经成功地
从OspA免疫的P. leucopus,推测为P.白足
胚胎干细胞,并显示白蛋白位点似乎适合抗体分泌
从肝脏。我们现在寻求(1)鉴定结合至少四种不同OspA的抗体
表位,(2)建立稳定的胚胎干细胞系并进行种系编辑,以及(3)
产生遗传抗性小鼠,所述小鼠表达来自连接到
相互染色体易位,高阈值基因驱动的自然发生形式
这将使野生P的可逆和紧密定位的工程。白足
人口。我们的开放和社区指导的方法受到了明显的热情,
南图克特和玛莎葡萄园岛的居民,表明当地社区遭受
蜱传疾病在整个东北部和上中西部可能希望免疫他们的
几十年来,他们一直拥有野生小鼠种群,以帮助预防莱姆病。
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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Kevin Esvelt其他文献
Kevin Esvelt的其他文献
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{{ truncateString('Kevin Esvelt', 18)}}的其他基金
Heritable immunization of the white-footed mouse reservoir of Lyme disease
白足小鼠莱姆病储库的遗传免疫
- 批准号:
10674208 - 财政年份:2021
- 资助金额:
$ 88.1万 - 项目类别:
Heritable immunization of the white-footed mouse reservoir of Lyme disease
白足小鼠莱姆病储库的遗传免疫
- 批准号:
9989482 - 财政年份:2021
- 资助金额:
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EVOLVING VIRUS-SPECIFIC sACE2 MIMICS FOR COMPETITIVE INHIBITION OF SARS-CoV-2
进化病毒特异性 sACE2 模拟物以竞争性抑制 SARS-CoV-2
- 批准号:
10175307 - 财政年份:2020
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Developing powerful daisy drive systems for the precise alteration of local populations
开发强大的雏菊驱动系统以精确改变当地人口
- 批准号:
10085329 - 财政年份:2017
- 资助金额:
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Sculpting the Enteric Microbiota with CRISPR-Cas Systems
使用 CRISPR-Cas 系统塑造肠道微生物群
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9267984 - 财政年份:2016
- 资助金额:
$ 88.1万 - 项目类别:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
使用 CRISPR-Cas 系统塑造肠道微生物群
- 批准号:
9198068 - 财政年份:2016
- 资助金额:
$ 88.1万 - 项目类别:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
使用 CRISPR-Cas 系统塑造肠道微生物群
- 批准号:
8751445 - 财政年份:2014
- 资助金额:
$ 88.1万 - 项目类别:
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