Mendelian inheritance of artificial chromosomes
人工染色体的孟德尔遗传
基本信息
- 批准号:10487450
- 负责人:
- 金额:$ 116.96万
- 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:2021-09-10 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelAnimalsAreaArtificial ChromosomesArtificial Mammalian ChromosomesBehaviorBiological ModelsBiotechnologyCell divisionCentromereChromatinChromosome PairingChromosomesCircular DNAClinicCustomDNADNA SequenceDataDevelopmentElementsEmbryoEnsureEpigenetic ProcessEukaryotaFemaleFoundationsGenesGeneticGenetic RecombinationGenomeGenome ComponentsGenome engineeringGerm CellsGoalsGoldHarvestHistonesHuman ChromosomesHuman Genome ProjectIn VitroIndustrializationInheritedInvestmentsLawsMammalian CellMammalian ChromosomesMammalsMedicineMeiosisMitosisMitoticMitotic Cell CycleMusNucleic Acid Sequence HomologyNucleosomesOrgan TransplantationOutcomePatientsPrivatizationProblem SolvingProphaseResearch PersonnelResearch Project GrantsSaccharomycetalesSex ChromosomesSexual ReproductionSourceSpecific qualifier valueTechnologyTestingTimeVariantWorkWritingYeastscentromere protein Adesigndrug developmentfrontiergenetic elementgenetic payloadin vivoinnovationinsightmouse modelquantumsegregationsuccesssynthetic biologysynthetic constructtelomeretooltransmission processvector
项目摘要
Synthetic mammalian artificial chromosomes (MACs) represent a new frontier in genome technology,
with the potential to transform chromosome and synthetic biology and stimulate the development of numerous
radical advances in medicine. Human Genome Project-Write aims to generate an entire set of synthetic human
chromosomes. Short of this ambitious goal, MACs have enormous potential for breakthroughs in biotechnology
and medicine, such as creating humanized animal models for drug development or for harvesting patient-
personalized organs for transplantation. Furthermore, building MACs from minimal components will advance
our fundamental understanding of what comprises a mammalian chromosome.
As vehicles for genetic inheritance, fully functional chromosomes are faithfully transmitted through
mitosis and the specialized meiotic divisions underlying eukaryotic sexual reproduction and Mendelian
inheritance. Our goal is to construct the first MACs that achieve faithful inheritance through the germline, using
mouse as a model system. One obstacle is the centromere, the locus on each chromosome that directs
transmission through both mitosis and meiosis. Because mammalian centromeres are not encoded in the DNA
sequence, it is unclear how to build synthetic chromosomes containing this crucial element. There are
additional challenges to create MACs that pair and recombine as homologous chromosomes in meiosis. To
solve these problems, we will hijack the existing cellular machinery for assembling centromere chromatin and
incorporate additional genetic elements to ensure meiotic pairing and recombination.
This effort requires innovation at multiple levels: designing MAC vectors encoding key functional
elements, assembling large synthetic DNA constructs, and ultimately creating animals to test MACs in vivo.
The proposed work builds on recent advances from the co-investigators’ teams in all of these areas, and we
have key tools and expertise in place to build the necessary DNA templates, introduce them into embryos,
analyze the outcomes, and develop alternative strategies as necessary. The most meaningful preliminary data
would be to show a synthetic artificial chromosome that is successfully transmitted through mitosis and meiosis
in vivo, but achieving this step is a major goal of our proposal and will require substantial investment of time
and effort. Thus, we are requesting support for this project without the preliminary data that would demonstrate
high likelihood of success, justifying consideration of our proposal as part of the T-R01 mechanism.
We use mouse as a relatively rapid and tractable mammalian model system with outstanding
opportunities for testing and debugging MACs, and our advances should readily transfer to other species for
applications in biotechnology and medicine. Success in this project will represent a quantum leap in the
development of synthetic artificial chromosome that are fully functional in vivo, providing unprecedented
genome engineering capabilities in animal models and enabling diverse synthetic biology applications.
合成哺乳动物人工染色体(Mac)代表了基因组技术的一个新前沿,
有可能改变染色体和合成生物学,并刺激无数
医学上的突破性进展。人类基因组计划-WRITE旨在产生一套完整的人造人类
染色体。如果不能实现这一雄心勃勃的目标,Mac在生物技术方面有巨大的突破潜力。
以及医学,例如为药物开发或采集患者创造人性化的动物模型-
个人化器官移植。此外,从最少的组件构建Mac将会取得进展
我们对哺乳动物染色体组成的基本理解。
作为遗传的载体,功能齐全的染色体通过
有丝分裂与真核有性生殖和孟德尔的减数分裂
继承。我们的目标是构建第一个通过生殖系实现忠实遗传的Mac,使用
以鼠标为模型系统。一个障碍是着丝粒,即每条染色体上指向
通过有丝分裂和减数分裂进行传播。因为哺乳动物着丝粒不是在DNA中编码的
目前尚不清楚如何构建包含这一关键元件的合成染色体。确实有
在减数分裂中创造作为同源染色体配对和重组的Mac的额外挑战。至
解决这些问题,我们将劫持现有的细胞机器来组装着丝粒染色质和
加入更多的遗传因素,以确保减数分裂配对和重组。
这项工作需要在多个层面上进行创新:设计编码关键函数的MAC向量
元素,组装大型合成DNA结构,并最终创造出在体内测试Mac的动物。
拟议的工作建立在联合调查组在所有这些领域取得的最新进展的基础上,我们
有关键的工具和专业知识来构建必要的DNA模板,将它们引入胚胎,
分析结果,并根据需要制定替代战略。最有意义的初步数据
将显示一个人造染色体,它通过有丝分裂和减数分裂成功地传播
但实现这一步是我们建议的一个主要目标,需要大量的时间投入
和努力。因此,我们请求在没有初步数据的情况下为这个项目提供支持
成功的可能性很高,有理由考虑将我们的建议作为T-R01机制的一部分。
我们使用小鼠作为一个相对快速和易处理的哺乳动物模型系统,具有出色的
测试和调试Mac的机会,我们的进步应该很容易转移到其他物种
在生物技术和医学方面的应用。这个项目的成功将代表着在
开发在体内具有全功能的人造染色体,提供前所未有的
在动物模型中的基因组工程能力,并使不同的合成生物学应用。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ben E. Black其他文献
A high-resolution look at fresh human brain vitrified directly from autopsy using cryo-electron tomography with cryo-plasma focused ion beam milling
- DOI:
10.1016/j.bpj.2023.11.1192 - 发表时间:
2024-02-08 - 期刊:
- 影响因子:
- 作者:
Benjamin C. Creekmore;Kathryn Kixmoeller;Ben E. Black;Edward B. Lee;Yi-Wei Chang - 通讯作者:
Yi-Wei Chang
A PARP2 active site helix melts to permit DNA damage-induced enzymatic activation
PARP2 活性位点螺旋熔化以允许 DNA 损伤诱导的酶促激活
- DOI:
10.1016/j.molcel.2025.01.004 - 发表时间:
2025-03-06 - 期刊:
- 影响因子:16.600
- 作者:
Emily S. Smith-Pillet;Ramya Billur;Marie-France Langelier;Tanaji T. Talele;John M. Pascal;Ben E. Black - 通讯作者:
Ben E. Black
Remodeling of inner kinetochore components at mitotic onset is required for chromosome segregation
- DOI:
10.1016/j.bpj.2023.11.2240 - 发表时间:
2024-02-08 - 期刊:
- 影响因子:
- 作者:
Praveen Kumar Allu;Lucie Y. Guo;Rachel M. Lackner;David M. Chenoweth;Ben E. Black - 通讯作者:
Ben E. Black
Satellite DNA shapes dictate pericentromere packaging in female meiosis
卫星 DNA 形状决定着女性减数分裂中着丝粒周围区域的包装
- DOI:
10.1038/s41586-024-08374-0 - 发表时间:
2025-01-08 - 期刊:
- 影响因子:48.500
- 作者:
Damian Dudka;Jennine M. Dawicki-McKenna;Xueqi Sun;Keagan Beeravolu;Takashi Akera;Michael A. Lampson;Ben E. Black - 通讯作者:
Ben E. Black
Centromeric chromatin clearings demarcate the site of kinetochore formation
着丝粒染色质间隙划定了动粒形成的位点。
- DOI:
10.1016/j.cell.2024.12.025 - 发表时间:
2025-03-06 - 期刊:
- 影响因子:42.500
- 作者:
Kathryn Kixmoeller;Ekaterina V. Tarasovetc;Elie Mer;Yi-Wei Chang;Ben E. Black - 通讯作者:
Ben E. Black
Ben E. Black的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ben E. Black', 18)}}的其他基金
Core 2: Mammalian Artificial Chromosome (MAC)
核心 2:哺乳动物人工染色体 (MAC)
- 批准号:
10626286 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Tuning PARP-1 retention and release on DNA breaks
调节 DNA 断裂时 PARP-1 的保留和释放
- 批准号:
10363534 - 财政年份:2022
- 资助金额:
$ 116.96万 - 项目类别:
Tuning PARP-1 retention and release on DNA breaks
调节 DNA 断裂时 PARP-1 的保留和释放
- 批准号:
10581522 - 财政年份:2022
- 资助金额:
$ 116.96万 - 项目类别:
Mendelian inheritance of artificial chromosomes
人工染色体的孟德尔遗传
- 批准号:
10666591 - 财政年份:2021
- 资助金额:
$ 116.96万 - 项目类别:
Mendelian inheritance of artificial chromosomes
人工染色体的孟德尔遗传
- 批准号:
10272686 - 财政年份:2021
- 资助金额:
$ 116.96万 - 项目类别:
Structural biology and molecular biophysics training program
结构生物学和分子生物物理学培训计划
- 批准号:
10630348 - 财政年份:2019
- 资助金额:
$ 116.96万 - 项目类别:
Structural biology and molecular biophysics training program
结构生物学和分子生物物理学培训计划
- 批准号:
10192759 - 财政年份:2019
- 资助金额:
$ 116.96万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 116.96万 - 项目类别:
Grant-in-Aid for Early-Career Scientists