Molecular Regulators of Renal Collecting Duct Differentiation and Maintenance
肾集合管分化和维护的分子调节剂
基本信息
- 批准号:9173773
- 负责人:
- 金额:$ 36.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultBiomedical EngineeringCell Culture TechniquesCell Differentiation processCell LineCell LineageCell MaintenanceCellsDevelopmentDiseaseDuct (organ) structureEctopic ExpressionElectrolytesEnd stage renal failureEngineeringFactor XGene Expression ProfilingGenesGoalsIn VitroIntercalated CellKidneyKidney TransplantationKnowledgeMaintenanceMediatingMesenchymeMetanephric DiverticulumMethodsModelingMolecularMusPatientsPositioning AttributePublishingSignal PathwaySignal TransductionStagingStem cellsSurvival RateTestingUnited StatesWateractivating transcription factorbasecell typecollecting tubule structuredesignimprovedin vivoinduced pluripotent stem cellmouse modelnotch proteinpH Homeostasispromoterregenerativetranscription factortranscriptomevasopressin resistant diabetes insipidus
项目摘要
Summary
Approximately 101,000 people are waitlisted for a kidney transplant in the United States, while only
about 17,000 kidney transplants took place in 2013. This shortage of transplantable kidneys can be overcome
by differentiating kidneys from patient derived induced pluripotent-stem cells to improve survival rates of end
stage renal disease (ESRD) patients. Since kidneys develop from the ureteric bud (UB) and metanephric
mesenchyme (MM), we need to make the different cell types that differentiate from the UB and MM to engineer
kidneys in culture. Our goal is to understand the molecular mechanisms regulating kidney collecting duct
differentiation into principal cells (PCs) and intercalated cells (ICs). This knowledge will be used to establish
methods to convert UB cells into PCs and ICs in culture. We hypothesize that PC promoting signals (Signal-P)
co-operate with Notch to activate Elf5 expression and other PC lineage transcription factors (PCFs) to promote
PC differentiation (Fig.1). Ectopic expression of activated Notch1 turns on Hes1 and Elf5 among other
candidate PCFs to induce precocious PC differentiation in developing CDs in vivo, but is unable to turn on Elf5
or other PC specific genes in cultured immature UB cells. Notch signaling suppresses Foxi1 (an essential IC
factor), other candidate IC transcription factors (ICFs), and components of candidate signaling pathways
(Signal-I) that promote IC differentiation. In Aim1 the early regulators of collecting duct differentiation that turn
on Elf5, an early PC marker, and Foxi1, an early intercalated cell (IC) marker, will be determined. Aim2 focuses
on determining intermediate regulators of PC and IC differentiation by examining the contribution of Foxi1, Elf5
and Hes1 to collecting duct differentiation using genetically modified mice, UB cells, and mature PC and IC
lines. In Aim3 we will determine how mature PCs are maintained. We have evidence implicating Notch
signaling in maintenance of mature PC cell state. This will be verified by conditional inactivation of Notch
signaling in adult CDs and the mechanisms of Notch mediated PC maintenance will be determined. A mouse
model of acquired Nephrogenic Diabetes Insipidus (aNDI) in which mature PCs are reduced, potentially due to
cell fate switching, will be used to determine which CD differentiation factors are involved in PC maintenance.
By lineage tracing we will definitively determine whether PC to IC fate change occurs during aNDI. These
studies are not merely incremental but provide a transformative step in our understanding of collecting duct
development and maintenance.
概括
大约有101,000人在美国等待着肾脏移植
2013年进行了大约17,000个肾脏移植。可以克服这种可移植肾脏的短缺
通过将肾脏与患者衍生的诱导多能茎细胞区分开来提高终点的存活率
阶段肾脏疾病(ESRD)患者。由于肾脏从输尿管芽(UB)和Metanephric发育
间充质(MM),我们需要制作不同的单元格类型,这些类型从UB和MM到工程师
文化中的肾脏。我们的目标是了解调节肾脏收集管的分子机制
分化为主要细胞(PC)和插入细胞(ICS)。这些知识将用于建立
将UB细胞转换为PC和培养物中IC的方法。我们假设PC促进信号(Signal-P)
与Notch合作激活ELF5表达和其他PC谱系转录因子(PCF)以促进
PC分化(图1)。激活Notch1的异位表达在HES1和ELF5上旋转
候选PCF在体内开发CD时会引起早熟的PC差异化,但无法打开ELF5
或培养的未成熟UB细胞中的其他PC特定基因。 Notch信号抑制FOXI1(一个必不可少的IC
因素),其他候选IC转录因子(ICF)和候选信号通路的组成部分
(Signal-I)促进IC分化。在AIM1中,收集管道差异化的早期调节器转弯
在ELF5上,将确定早期的PC标记和FOXI1(IC)标记。 AIM2聚焦
通过检查FOXI1,ELF5的贡献来确定PC的中间调节器和IC差异化
HES1使用转基因的小鼠,UB细胞以及成熟的PC和IC收集管道分化
线。在AIM3中,我们将确定如何维护成熟的PC。我们有证据牵涉到缺口
维持成熟PC细胞状态的信号传导。这将通过有条件灭活Notch来验证
将确定成人CD的信号传导以及Notch介导的PC维护的机制。鼠标
获得的肾原性糖尿病模型(ANDI),其中成熟的PC被降低,可能是由于
细胞命运切换将用于确定PC维护中涉及哪些CD分化因子。
通过谱系追踪,我们将一定会确定在Andi期间是否发生PC到IC命运变化。这些
研究不仅是增量的
开发和维护。
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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Kameswaran Surendran其他文献
Kameswaran Surendran的其他文献
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{{ truncateString('Kameswaran Surendran', 18)}}的其他基金
Molecular and cellular basis of the renal diseases associated with Alagille Syndrome
阿拉吉尔综合征相关肾脏疾病的分子和细胞基础
- 批准号:
10617239 - 财政年份:2021
- 资助金额:
$ 36.34万 - 项目类别:
Molecular and cellular basis of the renal diseases associated with Alagille Syndrome
阿拉吉尔综合征相关肾脏疾病的分子和细胞基础
- 批准号:
10209370 - 财政年份:2021
- 资助金额:
$ 36.34万 - 项目类别:
Molecular and cellular basis of the renal diseases associated with Alagille Syndrome
阿拉吉尔综合征相关肾脏疾病的分子和细胞基础
- 批准号:
10399602 - 财政年份:2021
- 资助金额:
$ 36.34万 - 项目类别:
Molecular Regulators of Renal Collecting Duct Differentiation and Maintenance
肾集合管分化和维持的分子调节剂
- 批准号:
9305081 - 财政年份:2016
- 资助金额:
$ 36.34万 - 项目类别:
The cellular and molecular mechanisms regulating renal proximal tubule.........
调节肾近曲小管的细胞和分子机制.........
- 批准号:
8465608 - 财政年份:
- 资助金额:
$ 36.34万 - 项目类别:
The cellular and molecular mechanisms regulating renal proximal tubule morphogenesis
调节肾近曲小管形态发生的细胞和分子机制
- 批准号:
8725207 - 财政年份:
- 资助金额:
$ 36.34万 - 项目类别:
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