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 These observations for the role of Ebf1 in kidney development were originally made by the applicant, Dr.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.

Public Health Relevance

We have identified the transcriptional regulator Early B Cell Factor 1 (Ebf1) as a completely novel key participant in renal development and podocyte function. Currently an estimated 11.5 percent of adults ages 20 or older have physiological evidence of chronic kidney disease, while congential nephritic syndrome has a prevalence of 16 per 100,000 children. Investigation into the mechanisms underlying Ebf1's role in disease progression will be instrumental to increasing the potential for more effective clinical treatments for management of renal disorders effecting podocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
4R00DK093711-03
Application #
8844133
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hoshizaki, Deborah K
Project Start
2012-07-15
Project End
2017-06-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$248,999
Indirect Cost
$99,450
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520