Development and validation of genetic cell ablation systems in axolotl
蝾螈遗传细胞消融系统的开发和验证
基本信息
- 批准号:10592336
- 负责人:
- 金额:$ 20.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAmbystomaApoptosisAutomobile DrivingBackBrainCell CommunicationCell LineageCellsCommunitiesComplexComplex MixturesConnective TissueConnective Tissue CellsDepositionDevelopmentDiphtheriaEngineeringEnzymesEyeGeneticGenomicsHealthHeartHumanImmuneKidneyLaboratoriesLimb structureLungMammalsMetronidazoleModernizationMuscleMuscle FibersMuscle satellite cellNatural regenerationNewtsNitroreductasesNormal CellOrganPatternPharmaceutical PreparationsPhenotypePopulationProcessProteinsPublishingResearchRoleSourceSpinal CordSystemTailTissue ModelTissuesToxinTransgenic OrganismsTranslatingValidationWorkappendageblastemacell injurycell regenerationcell typediphtheria toxin receptorexperimental studyimmunoregulationinducible Creinjury and repairinterestlimb regenerationmuscle formmuscle regenerationnovelorgan regenerationprogenitorreconstitutionregenerativeregenerative biologysatellite cellspatiotemporaltissue regenerationtool
项目摘要
Abstract:
The axolotl is a classical and robust model of tissue regeneration. Axolotls are well known for studies of limb
regeneration but also regenerate their eyes, lungs, heart, kidney, spinal cord, brain and provide a system to
study immune regulation of regeneration of all body tissues and organs. Studying mechanisms of regeneration
in axolotl provides a roadmap for engineering similar regeneration mechanisms in mammals and ultimately
humans. Two key questions in regeneration biology that remain incompletely understood are: (1). What are the
sources of replacement cells during injury repair? and (2). How do cells interact during regeneration to create
complex tissues that function as well as the original organs? Our work on generating transgenic axolotl has
brought this classical system into the modern genomic era where we can now lineage trace cells that
contribute to regeneration and start to tease apart specific regeneration mechanisms in different organs.
However, to fully understand the contribution of different cell types and lineages to regeneration, cell ablation
approaches are required. Cell ablation allows us to ask questions such as: What is the role of a specific cell
type in a complex mixture of cells during regeneration? Is a certain cell type necessary for organ/appendage
regeneration? Can other cells act as a reserve pool when the cell type that normally participates in the
regenerative process is missing? How do different cell types contribute to the overall patterning of the organ or
tissue regenerate? To answer these important questions, we propose generating broadly applicable transgenic
axolotl tools for lineage specific cell ablation studies. These tools either utilize enzymes that produces toxins or
make use of proteins/toxins that activate/induce cell apoptosis. Specifically, we will generate nitroreductase
(NTR) or Diphtheria toxin receptor (DTR) transgenic axolotls under LoxP control and cross them with tissue
specific inducible Cre lines that are already available in our laboratory to specifically express DTR or NTR in
the tissue of interest. This will provide us spatial control over cell ablation. Further by providing metronidazole
(drug) or diphtheria (toxin) respectively to NTR and DTR lines, we will be able to achieve temporal control.
Such spatiotemporal control of cell ablation can be achieved over any cell type if an inducible Cre line is
available for the tissue of interest. Hence, we believe that the development of genetic cell ablation systems in
axolotl will open doors for studying a wide variety of organs and appendages for example, limb, tail, eye, lung,
heart, kidney, spinal cord, brain and the role of immune cells in axolotl tissue regeneration.
摘要:
美西螈是组织再生的经典和强大的模型。蝾螈以研究四肢
再生,而且还再生他们的眼睛、肺、心脏、肾脏、脊髓、大脑,并提供一个系统,
研究所有身体组织和器官再生的免疫调节。研究再生机制
为在哺乳动物中设计类似的再生机制提供了路线图,
人类再生生物学中两个尚未完全理解的关键问题是:(1)。有哪些
损伤修复过程中的替代细胞来源?和(2)。细胞如何在再生过程中相互作用,
复杂组织的功能和原始器官一样吗我们在培育转基因蝾螈方面的工作
把这个经典的系统带入了现代基因组时代,我们现在可以追踪细胞的谱系,
有助于再生,并开始梳理不同器官的特定再生机制。
然而,为了充分了解不同细胞类型和谱系对再生的贡献,
需要采取一些办法。细胞消融使我们能够提出这样的问题:特定细胞的作用是什么
在再生过程中输入复杂的细胞混合物?某种细胞类型是器官/附件所必需的吗?
再生?当通常参与细胞库的细胞类型被破坏时,
再生过程缺失了吗不同类型的细胞如何影响器官的整体结构,
组织再生为了回答这些重要的问题,我们建议产生广泛适用的转基因,
美西螈的工具,用于谱系特异性细胞消融研究。这些工具要么利用产生毒素的酶,
利用激活/诱导细胞凋亡的蛋白质/毒素。具体来说,我们将产生硝基还原酶,
(NTR)或白喉毒素受体(DTR)转基因蝾螈在LoxP控制下,并将它们与组织
我们的实验室中已经可以获得特异性表达DTR或NTR的特异性诱导型Cre系,
目标组织这将为我们提供对细胞消融的空间控制。进一步通过提供甲硝唑
如果将白喉(药物)或白喉(毒素)分别作用于NTR和DTR系,我们将能够实现时间控制。
细胞消融的这种时空控制可以在任何细胞类型上实现,如果诱导型Cre系是
可用于感兴趣的组织。因此,我们认为,基因细胞消融系统的发展,
蝾螈将为研究各种器官和附属物打开大门,例如肢体,尾巴,眼睛,肺,
心脏、肾脏、脊髓、大脑以及免疫细胞在蝾螈组织再生中的作用。
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)
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Prayag Murawala其他文献
Prayag Murawala的其他文献
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{{ truncateString('Prayag Murawala', 18)}}的其他基金
Development and validation of genetic cell ablation systems in axolotl
蝾螈遗传细胞消融系统的开发和验证
- 批准号:
10452313 - 财政年份:2022
- 资助金额:
$ 20.75万 - 项目类别:
Understanding the role of thyroid hormone signaling during axolotl limb regeneration
了解甲状腺激素信号在蝾螈肢体再生过程中的作用
- 批准号:
10229238 - 财政年份:2020
- 资助金额:
$ 20.75万 - 项目类别:
Understanding the role of thyroid hormone signaling during axolotl limb regeneration
了解甲状腺激素信号在蝾螈肢体再生过程中的作用
- 批准号:
10437786 - 财政年份:2013
- 资助金额:
$ 20.75万 - 项目类别:
Understanding the role of thyroid hormone signaling during axolotl limb regeneration
了解甲状腺激素信号在蝾螈肢体再生过程中的作用
- 批准号:
10229325 - 财政年份:2013
- 资助金额:
$ 20.75万 - 项目类别:
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