Regulation of Podocyte Differentiation by the Transcription Factor EBF1

转录因子 EBF1 对足细胞分化的调节

• 批准号: 8507227
• 负责人: Jackie Fretz
• 金额: $ 9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507227
• 关键词: Adipocytes; Adult; Age; Age-Months; Albumins; Albuminuria; Animals; Apoptosis; B-Lymphocytes; Biochemistry; Biology; Blood Urea Nitrogen; Cell Lineage; Cell physiology; Cells; Cellular Structures; ChIP-seq; Child; Chronic Kidney Failure; Clinical Treatment; Commit; Core Facility; Cues; Defect; Development; Disease Progression; Distal convoluted renal tubule structure; Duct (organ) structure; Early identification; Education; Embryo; Ensure; Epithelial; Epithelium; Event; Exhibits; Faculty; Failure; Funding; Future; Gene Expression; Gene Targeting; Genes; Genome; Goals; Grant; Histology; In Vitro; Investigation; Investments; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Life; Mediating; Medical; Mentors; Mesenchymal; Mesenchyme; Metabolic; Metanephric Diverticulum; Metanephric structure; Molecular; Molecular Biology; Monitor; Morphogenesis; Mus; N-Cadherin; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrons; Organogenesis; Osteoblasts; Participant; Pathologist; Pathology; Pathway interactions; Pattern; Performance; Phenotype; Physical condensation; Physiological; Population; Positioning Attribute; Postdoctoral Fellow; Prevalence; Process; Protein Family; Proteins; Proteinuria; RNA; Regulation; Renal function; Reporter; Research; Research Personnel; Response Elements; Role; Scientist; Signal Pathway; Signal Transduction; Staging; Syndrome; Techniques; Time; Tissue Differentiation; Tissues; Training; Transcript; Transcriptional Regulation; Transfection; Tubular formation; Undifferentiated; Vascularization; Work; blastema; career; cell type; cytokine; design; epithelial to mesenchymal transition; genome analysis; in vivo; interstitial cell; kidney cell; mesangial cell; migration; nephrogenesis; novel; podocyte; postnatal; progenitor; protein expression; research study; transcription factor; wasting

DESCRIPTION (provided by applicant): The mature metanephros forms though the outgrowth of the ureteric bud into the metanephric mesenchyme which consequently condenses, undergoes mesenchymal to epithelial transition, and fuses to outgrowths of the bud to form the mature nephron. Multiple coordinated signaling pathways, cytokines and transcription factors have been identified as integral to this processes, however we present here our identification of Early B cell Factor 1 (Ebf1) as a completely novel transcription factor that is required for proper glomerular maturation. In the absence of Ebf1 kidneys develop with thinned cortices, reduced glomerular maturation, and nephrogenic blastema that persist into adulthood. The glomeruli that form present with dysfunctional vascularization, crescents, severely effaced podocytes, and these mice exhibit albuminuria and elevated blood urea nitrogen. We believe that Ebf1 is functioning during an intermediate to late stage of podocyte differentiation. This proposal contains two specific aims designed to (1) identify the stage in nephrogenesis in which Ebf1 functions to direct podocyte maturation, (2) identify the direct targets of Ebf1 within the podocyte, and ascertain the transcriptional consequences underlying the phenotype we have observed. These observations for the role of Ebf1 in kidney development were originally made by the applicant, Dr. Jackie A. Fretz. She has background in biochemistry and molecular biology focused on investigation of transcriptional regulation in multiple cell types and lineages, and is currently an Associate Research Scientist, a non-independent position, working under the direction of Dr. Mark Horowitz (mentor), an osteoimmunologist. In Dr. Horowitz's laboratory Dr. Fretz has made substantial progress into understanding the role of Ebf1 in the mechanisms directing cell fate choices of osteoblasts and adipocytes, and investigation of the role of Ebf1 in renal development presents a clear point of independence for Dr. Fretz to branch out and become an independent Investigator. To achieve this goal a multi-disciplinary mentoring committee has been formed to support the further training and eventual independence of Dr. Fretz. This committee includes, in addition to the primary mentor, 2 nephrologists, a renal pathologist, and developmental biologist. Dr. Fretz is currently located at Yale which is uniquely suited to achieve the proposed aims, not only for the world- renowned faculty that work there and have agreed to mentor the applicant, but also because of the numerous core facilities located in close proximity to each other and available to the applicant. These include histology laboratories, genome analysis centers, a first-class renal pathology facility, a mouse metabolic phenotyping center, and Yale also contains an NIDDK funded O'Brien Center for Kidney Research which specializes in performance and dissemination of techniques relevant to investigation of kidney function. Dr. Fretz's immediate career goal is to obtain a tenure-track faculty position at an academic or medical facility after her training is completed. Her ultimate career goals are to investigate transcriptional regulation of renal cell fates by the Ebf family of proteins. The applicant is committed to research into renal biology, transcriptional regulation, and to the education of future scientists. Receipt of the K99/R00 training grant will be instrumental to achieving these career goals and setting this scientist on her own pathway to independence.

描述（由申请人提供）：成熟的跨e鸟形成了输尿管芽的生长，从而进入元素间充质，因此凝结，经历间质向上皮过渡，并融合以形成成熟的肾单位。多个协调的信号通路，细胞因子和转录因子已被确定为这一过程不可或缺的组成部分，但是我们在这里介绍了早期B细胞因子1（EBF1）的鉴定，这是完全新颖的转录因子，这是适当的转录因子 肾小球成熟。在没有EBF1肾脏的情况下，肾脏会稀薄，肾小球成熟减少以及持续到成年的肾病性囊肿。形成的肾小球具有功能失调的血管形成，新月形，严重脱落的足细胞，这些小鼠表现出蛋白尿和血液尿素氮的升高。我们认为，在足细胞分化的中间至后期中，EBF1正在运行。该提案包含两个特定目的，旨在（1）确定肾脏发生的阶段，在该肾上腺生成中，EBF1在直接足细胞成熟的情况下起作用，（2）确定我们观察到的表型的转录后果，确定了Podocyte内EBF1的直接目标。这些对EBF1在肾脏发育中作用的观察最初是由申请人Jackie A. Fretz博士进行的。她具有生物化学和分子生物学背景，重点是研究多种细胞类型和谱系中的转录调节，目前是一个非独立的研究科学家，是一个非独立的位置，在马克·霍洛维茨（Mark Horowitz）（Mentor）的指导下工作，是一种骨气免疫学家Mark Horowitz（Mentor） 。在霍洛维茨博士的实验室中，弗雷茨博士在理解EBF1在指导成骨细胞和脂肪细胞的细胞命运选择的机制中的作用取得了重大进展，并研究了EBF1在 肾发展为弗雷茨博士分支并成为独立研究员提供了明显的独立点。为了实现这一目标，已经成立了一个多学科指导委员会，以支持Fretz博士的进一步培训和最终独立性。该委员会还包括两家肾病学家，肾脏病理学家和发育生物学家。弗雷茨（Fretz）博士目前位于耶鲁大学，它非常适合实现拟议的目标，不仅是针对在那里工作并同意指导申请人的世界知名教师，而且还因为众多核心设施非常接近彼此，可供申请人使用。其中包括组织学实验室，基因组分析中心，一流的肾脏病理学设施，老鼠代谢表型中心和耶鲁大学还包含一个由NIDDK资助的O'Brien肾脏研究中心，该中心专门研究与肾脏研究相关的性能和传播功能。 Fretz博士的直接职业目标是在培训完成后，在学术或医疗机构获得终身任职的职位。她的最终职业目标是调查EBF家族对肾细胞命运的转录调节 蛋白质。申请人致力于研究肾脏生物学，转录调节和未来科学家的教育。收到K99/R00培训补助金将有助于实现这些职业目标，并将这位科学家置于自己的独立之路上。