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）：成熟的后肾通过输尿管芽的外生物形成后肾间质，后肾间质浓缩，经历间质向上皮的转变，并融合到芽的外生物形成成熟的肾元。多种协调的信号通路、细胞因子和转录因子已被确定为这一过程的组成部分，然而，我们在这里提出了我们确定的早期B细胞因子1 （Ebf1）是一种完全新颖的转录因子，是正确的转录所需的