Engineering erythropoietin-producing cells
Engineering erythropoietin-producing cells
批准号:
9516535
负责人:
Thomas Joseph Carroll
金额:
$29.16万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-08-15 至 2018-08-31
关键词:
Abdominal CavityAdultAlpha CellAnemiaBiological AssayBudgetsCell CountCell Differentiation processCell LineCell TherapyCellsCellular biologyChronic Kidney FailureClinicalDepressed moodDevelopmental ProcessEncapsulatedEngineeringEnterobacteria phage P1 Cre recombinaseErythrocytesErythropoietinEventFibroblastsFrequenciesFutureGeneticGenetic TranscriptionGoalsGrowthHeart ArrestHormonesHumanHypoxiaImplantInvestigationKidneyLabelLocationMedicareMicrospheresMolecularMolecular ProfilingMorbidity - disease rateMouse StrainsMusNephrectomyOrganoidsPatientsPolycythemiaPopulationProductionProtocols documentationRecombinant ErythropoietinReporterReportingSourceSpecific qualifier valueStimulusStrokeStromal CellsTamoxifenTechnologyTestingTissuesVariantadult stem cellcardiovascular risk factorcell typeclinical translationcosteconomic incentiveexperimental studygenetic analysisinduced pluripotent stem cellinterestkidney cellkidney medullanephrogenesisprecursor celltooltranscriptometranscriptome sequencingtumor
中文摘要
摘要
肾脏是成人促红细胞生成素(EPO)的主要来源。EPO产生损失
慢性肾病(CKD)患者中的红细胞会导致红细胞生成抑制,
发病率的贡献者。虽然CKD患者可以通过全身施用EPO来治疗,但这导致
激素可用性的零星和过度峰值,这可能为某些肿瘤提供生长刺激。在
此外,给予CKD患者重组EPO或EPO刺激剂(ESA)与
增加了心血管事件的风险,包括心脏骤停和中风。目前尚不清楚这些
疾病是由EPO刺激的红细胞数量过多(红细胞增多症)或脱靶引起的
EPO本身的作用最后,CKD患者使用重组EPO的成本现在代表了
占医疗预算的很大一部分。因此,有很强的临床和经济动机,
衍生诱导多能干细胞(iPSC)衍生的EPO产生细胞,其可用于治疗贫血,
CKD患者。我们建议确定条件,以产生EPO生产细胞的定向分化
通过重现在发育中的肾脏内指定这种细胞类型的发育过程。
遗传分析显示,肾EPO产生细胞(REPC)是一种位于肾组织的间质成纤维细胞,
在肾脏外髓质的近端小管周围。REPC来源于表达Foxd 1的基质细胞,
仅在活跃的肾脏发育期间存在的前体群体。REPC人群
由于EPO仅在缺氧时表达,而其他标记物特异性地
这些细胞缺乏。更深入地了解REPC的分子特性对于
定义iPSC定向分化的靶状态。因此,我们建议:定义分子
通过基因标记和分离的含氧量正常的REPC概况,和2.使用EPO-报告基因iPSC来测试
类器官分化方案产生缺氧响应性EPO产生细胞的能力。因为
产生EPO的细胞只在小鼠中被空间定义,我们看到这种串联方法使用了
小鼠遗传工具和从遗传修饰的人iPSC分化的类器官是必需的。的
实验在技术上是可行的,我们的团队在基质细胞生物学方面具有专业知识,这将是必不可少的。
发展分化条件。在短期内,我们的目标是通过以下方式对这些细胞进行功能测试:
将它们包封在微球中并将它们植入小鼠的腹腔中,
肾切除术从长远来看,我们的目标是将缺氧反应,EPO产生细胞纳入
用于临床转化的合成肾脏组织。
英文摘要
ABSTRACT
The kidney is the major source of erythropoietin (EPO) production in adults. Loss of EPO-producing
cells in chronic kidney disease (CKD) patients causes depressed red blood cell production and is a significant
contributor to morbidity. Although CKD patients can be treated by systemic administration of EPO, this leads to
sporadic and excessive peaks in hormone availability, which may provide growth stimuli to certain tumors. In
addition, administration of recombinant EPO or EPO stimulating agents (ESAs) to CKD patients is associated
with increased risk of cardiovascular events including cardiac arrest and stroke. It is not clear whether these
morbidities are caused by excessive red blood cell number (polycythemia) stimulated by EPO or off-target
effects of EPO itself. Finally, the cost of administering recombinant EPO to CKD patients now represents a
significant proportion of the Medicare budget. Therefore, there are strong clinical and economic incentives for
deriving an induced pluripotent stem cell (iPSC)-derived EPO-producing cell that could be used to treat anemic
CKD patients. We propose to define conditions to generate EPO-producing cells by directed differentiation
through recapitulating the developmental process that specifies this cell type within the developing kidney.
Genetic analyses have revealed that the renal EPO-producing cell (REPC) is a stromal fibroblast located
around proximal tubules in the outer medulla of the kidney. REPCs derive from the Foxd1-expressing stromal
precursor population that is present only during the period of active kidney development. The REPC population
has been difficult to identify because EPO is only expressed upon hypoxia, and other markers to specifically
identify these cells are lacking. A deeper understanding of the molecular identity of the REPC is essential to
define a target state for directed differentiation of iPSCs. We therefore propose to: 1. Define the molecular
profile of normoxic REPCs through genetic labelling and isolation, and 2. Use EPO-reporter iPSCs to test the
capacity of organoid differentiation protocols to generate hypoxia responsive EPO-producing cells. Because
the EPO-producing cell has only been spatially defined in the mouse, we see this tandem approach using both
mouse genetic tools and organoids differentiated from genetically modified human iPSCs as essential. The
experiments are technically feasible, and our group has expertise in stromal cell biology, which will be essential
to developing differentiation conditions. In the short term we would aim to functionally test these cells by
encapsulating them in microspheres and implanting them into the abdominal cavities of mice subjected to
nephrectomy. In the long term, we would aim to incorporate hypoxia-responsive, EPO-producing cells into
synthetic kidney tissue destined for clinical translation.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10260117
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资助金额:$53.03万
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财政年份:2020
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依托单位:
Mechanisms of Disease
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批准号:10654560
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资助金额:$19.43万
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Mechanisms of Disease
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依托单位:
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批准号:9981392
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财政年份:2015
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负责人:Thomas Joseph Carroll
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依托单位:
UTSW Summer Undergraduate Research Institute for the Study of Kidney Diseases
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批准号:8853278
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项目类别:
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资助金额:$10.08万
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负责人:Thomas Joseph Carroll
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依托单位:
UTSW Summer Undergraduate Research Institute for the Study of Kidney Diseases
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项目类别:
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资助金额:$10.08万
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财政年份:2014
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依托单位:
UTSW Summer Undergraduate Research Institute for the Study of Kidney Diseases
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资助金额:$10.08万
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财政年份:2014
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负责人:Thomas Joseph Carroll
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依托单位:
UTSW Summer Undergraduate Research Institute for the Study of Kidney Diseases
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资助金额:$12.96万
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财政年份:2014
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依托单位:
UTSW Summer Undergraduate Research Institute for the Study of Kidney Diseases
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资助金额:$12.96万
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财政年份:2014
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负责人:Thomas Joseph Carroll
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依托单位:
2014 ASN Advance in Research Conference
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依托单位:
UTSW Summer Undergraduate Research Institute for the Study of Kidney Diseases
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依托单位:
Delineating a role for non-canonical wnt signaling in PKD
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依托单位:
Delineating a role for non-canonical wnt signaling in PKD
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依托单位:
海外基金