Functional Analysis of the Role of Transcription Factor 21 (Tcf21) in Nephron Progenitor Cells in Congenital Anomalies of the Kidney and Urinary Tract
转录因子 21 (Tcf21) 在肾单位祖细胞中在肾脏和尿路先天性异常中的作用的功能分析
基本信息
- 批准号:10320976
- 负责人:
- 金额:$ 16.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnatomyBilateralBioinformaticsBiologicalBirthBreedingCardiovascular systemCaringCell Differentiation processCell LineageCell MaintenanceCellsChildChildhoodChronic Kidney FailureClinicalComputational BiologyCongenital AbnormalityDataDefectDevelopmentDevelopmental BiologyDialysis procedureDistalDoctor of PhilosophyDown-RegulationDysplasiaEndowmentEnsureEnvironmentEpithelialEquilibriumExhibitsExtramural ActivitiesFundingGene Expression ProfilingGenesGeneticGenomicsGoalsHeadHeterogeneityHumanHypertensionImmunologyIndividualInstitutesIntentionInternationalK-Series Research Career ProgramsKidneyKidney FailureKidney TransplantationKnowledgeLeadLifeLongevityMaintenanceMediatingMentorsMesenchymeMetanephric DiverticulumMethodsModelingMolecularMolecular AnalysisMolecular BiologyMorphologyMosaicismMusNatural regenerationNephrologyNephronsOrganoidsPathogenesisPathway AnalysisPathway interactionsPatientsPatternPhenotypePositioning AttributePregnancyPreventionProphylactic treatmentRNA analysisRegulationResearchResearch PersonnelResearch TrainingResolutionRestRoleSchoolsSeriesSeveritiesSignal TransductionStromal CellsSurvival RateTechnologyTestingTherapeuticTimeTrainingTransplantationUniversitiesUp-RegulationUrinary tractVesico-Ureteral RefluxWNT Signaling PathwayWorkbasebeta catenincareercongenital anomalies of the kidneycurative treatmentsearly onsetexperiencegain of functiongenetic analysisin vivokidney cellloss of functionmedical schoolsmouse modelmultidisciplinarymultipotent cellnephrogenesisnephron progenitornew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspodocyteprematureprofessorprogenitorrenal agenesisself-renewalsingle-cell RNA sequencingskillsstem cell self renewalstem cellsstem-like cellsymposiumtranscription factoryoung adult
项目摘要
PROJECT SUMMARY/ABSTRACT
This is an application for a K08 Career Development Award for Gal Finer, MD, PhD, an Assistant
Professor at the Feinberg School of Medicine of Northwestern University. This applicant has clinical training in
Pediatric Nephrology and research training in immunology, genetics, and molecular biology. Her long-term
career goal is to become an independently funded researcher with expertise in renal development. This
proposal will position the applicant to gain advanced skills in developmental biology and pertinent experimental
methods. To achieve these goals, Dr. Finer has assembled a multidisciplinary mentoring team with expertise
in extramurally funded research, and she will be participating in coursework, seminars, and conferences.
The broad, long-term objectives of the project included in this career development award are to decipher
the molecular mechanisms that cause congenital anomalies of the kidney and urinary tract (CAKUT) and to
identify novel therapeutic targets. CAKUT is the leading cause of chronic kidney disease in the first three
decades of life and is associated with survival rate that is 30 times lower than that of healthy children. However,
very little is known about the pathogenesis of CAKUT, and in the absence of prevention or curative treatment,
care relies mainly on dialysis and transplantation. The nephron progenitor cells (NPCs) are multipotent cells
that are critical for ensuring normal nephron number and normal kidney size at birth. It has been shown that, in
normal development, these cells strike a balance between self-renewal and lineage-specific differentiation
(NPC dynamics). However, the basic mechanisms that control these “stem-like” cells are poorly understood.
The Quaggin lab has identified a novel bHLH transcription factor, Tcf21, that is critical for kidney development.
We preliminary show that Tcf21 controls the expression of Cited1 and Wnt4, two β-catenin targets that are
involved in NPC self-renewal and differentiation. The central hypothesis of this proposal is that Tcf21 controls
NPC dynamics by regulating Wnt/β-catenin signaling. We will utilize unique genetic mouse models of Tcf21-
depleted NPCs that present CAKUT-spectrum renal dysplasia to dissociate the effects of Tcf21 on NPC
differentiation. Our Specific Aims are to decipher the molecular mechanisms by which Tcf21 regulates NPCs.
To address our aims, we will perform molecular analysis of the β-catenin pathway, analysis of genetic breeding,
morphological analysis of the nephrogenic niche, lineage tracing, and single-cell RNA-sequencing.
This work will be mentored by Dr. Susan Quaggin, Head of the Division of Nephrology and Hypertension
and the Director of the Feinberg School Cardiovascular and Renal Institute at Northwestern University. Dr.
Quaggin is an internationally acclaimed developmental nephrologist with extensive mentoring experience. The
single-cell RNA analysis of this proposal will be mentored by Dr. Deborah Winter for her expertise in
computational biology and bioinformatics in genomic studies. This project will also benefit from the exceptional
research environment of Dr. Quaggin’s lab and the Northwestern University Feinberg School of Medicine.
项目总结/摘要
这是一份K 08职业发展奖的申请,申请人是Gal Finer,MD,PhD,助理
西北大学Feinberg医学院教授。申请人接受过以下方面的临床培训:
儿科肾病学和免疫学、遗传学和分子生物学的研究培训。她的长期
职业目标是成为一名独立资助的研究人员,具有肾脏发育方面的专业知识。这
提案将使申请人获得发育生物学和相关实验的高级技能
方法.为了实现这些目标,Finer博士组建了一个多学科的指导团队,
在校外资助的研究,她将参加课程,研讨会和会议。
这个职业发展奖中包含的项目的广泛,长期目标是破译
导致先天性肾脏和泌尿道异常(CAKUT)的分子机制,
确定新的治疗靶点。CAKUT是前三种慢性肾脏疾病的主要原因
寿命长达数十年,存活率比健康儿童低30倍。然而,在这方面,
关于CAKUT的发病机理知之甚少,并且在缺乏预防或治愈性治疗的情况下,
护理主要依靠透析和移植。肾单位祖细胞是一种多能细胞
这对于确保出生时正常的肾单位数量和肾脏大小至关重要。事实证明,在
正常发育时,这些细胞在自我更新和谱系特异性分化之间取得平衡
(NPC动力学)。然而,控制这些“干细胞样”细胞的基本机制知之甚少。
Quaggin实验室发现了一种新的bHLH转录因子Tcf 21,它对肾脏发育至关重要。
我们初步表明Tcf 21控制Cited 1和Wnt 4的表达,这两个β-连环蛋白靶点是
参与NPC的自我更新和分化。这个提议的中心假设是Tcf 21控制了
通过调节Wnt/β-catenin信号传导的NPC动力学。我们将利用独特的Tcf 21基因小鼠模型,
存在CAKUT谱肾发育不良的耗尽NPC,以分离Tcf 21对NPC的影响
分化我们的具体目标是破译Tcf 21调节NPC的分子机制。
为了实现我们的目标,我们将进行β-连环蛋白途径的分子分析,遗传育种分析,
肾发生生态位的形态学分析、谱系追踪和单细胞RNA测序。
这项工作将由肾脏病和高血压科主任Susan Quaggin博士指导
以及西北大学范伯格学院心血管和肾脏研究所的主任。博士
Quaggin是一位国际知名的发育肾病学家,拥有丰富的指导经验。的
本提案的单细胞RNA分析将由Deborah Winter博士指导,因为她在以下方面的专业知识:
基因组研究中的计算生物学和生物信息学。该项目还将受益于特殊的
Quaggin博士实验室和西北大学Feinberg医学院的研究环境。
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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Gal Finer其他文献
Gal Finer的其他文献
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{{ truncateString('Gal Finer', 18)}}的其他基金
Functional Analysis of the Role of Transcription Factor 21 (Tcf21) in Nephron Progenitor Cells in Congenital Anomalies of the Kidney and Urinary Tract
转录因子 21 (Tcf21) 在肾单位祖细胞中在肾脏和尿路先天性异常中的作用的功能分析
- 批准号:
9977390 - 财政年份:2020
- 资助金额:
$ 16.27万 - 项目类别:
Functional Analysis of the Role of Transcription Factor 21 (Tcf21) in Nephron Progenitor Cells in Congenital Anomalies of the Kidney and Urinary Tract
转录因子 21 (Tcf21) 在肾单位祖细胞中在肾脏和尿路先天性异常中的作用的功能分析
- 批准号:
10539273 - 财政年份:2020
- 资助金额:
$ 16.27万 - 项目类别:
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