Renal progenitor biology proffers valuable insight into the prevention and treatment of congenital kidney defects, which are among the leading causes of chronic renal failure in children. Much is known about the events that trigger the initial stages of kidney formation from gene targeting studies in mice. However, due to the complex nature of mammalian kidney development, there is a paucity of knowledge regarding how renal progenitors form mature nephrons-the fundamental units of the kidney that are made up of a series of discrete functional segments. The zebrafish model system provides a unique opportunity to discover how nephron segmentation occurs. Zebrafish embryos form an anatomically simple kidney of just two nephrons, which were recently shown to possess a segment organization akin to mammals. The zebrafish model is advantageous for loss- and gain-of-function genetic studies in renal progenitors due to the external fertilization and transparency of embryos, combined with the powerful molecular tools now available in this system. We propose to further characterize the nephron segment alterations in the retinoic acid (RA) deficient mutant, light bulb, and to determine the mechanisms by which renal progenitors respond to RA signaling during early stages of nephrogenesis. In addition, we will assign the roles and interrelationships between the Irx3b and Evi1 transcription factors in subsequent events of segment formation. The overall goal of this K01 application is to use the advantages of the zebrafish model to delineate the genetic pathways that direct nephron maturation by building a hierarchy of the pathways responsible for renal progenitor specification. This award will provide the candidate, Dr. Rebecca Wingert, a period of mentored research training in the laboratory of Dr. Alan Davidson, an experienced zebrafish biologist and emerging leader in nephrology. This training is essential for Dr. Wingert to develop the repertoire of skills to achieve her goal of becoming a successful, independent investigator with a research group dedicated to studying the developmental programs of renal progenitors and the application of this understanding to the origins and prevention/treatment of renal birth defects in humans.

Public Health Relevance

Knowledge of how the kidney develops is paramount to understanding kidney birth defects in humans, which commonly lead to kidney failure. The proposed research will determine how nephrons, the functional unit of the kidney, are properly formed during development. The understanding of this process has the potential to guide generation of therapies for kidney malformations and to prevent kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK083512-06
Application #
8435444
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2009-05-06
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
6
Fiscal Year
2013
Total Cost
$129,396
Indirect Cost
$9,585
Name
University of Notre Dame
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Miceli, R; Kroeger, Pt; Wingert, Ra (2014) Molecular Mechanisms of Podocyte Development Revealed by Zebrafish Kidney Research. Cell Dev Biol 3:
McCampbell, Kristen K; Springer, Kristin N; Wingert, Rebecca A (2014) Analysis of nephron composition and function in the adult zebrafish kidney. J Vis Exp :e51644
McKee, Robert; Gerlach, Gary F; Jou, Jonathan et al. (2014) Temporal and spatial expression of tight junction genes during zebrafish pronephros development. Gene Expr Patterns 16:104-13
Poureetezadi, Shahram Jevin; Donahue, Eric K; Wingert, Rebecca A (2014) A manual small molecule screen approaching high-throughput using zebrafish embryos. J Vis Exp :e52063
Marra, Amanda N; Wingert, Rebecca A (2014) Roles of Iroquois Transcription Factors in Kidney Development. Cell Dev Biol 3:1000131
Gerlach, Gary F; Wingert, Rebecca A (2014) Zebrafish pronephros tubulogenesis and epithelial identity maintenance are reliant on the polarity proteins Prkc iota and zeta. Dev Biol 396:183-200
Kroeger Jr, Paul T; Poureetezadi, Shahram Jevin; McKee, Robert et al. (2014) Production of haploid zebrafish embryos by in vitro fertilization. J Vis Exp :
Li, Yue; Cheng, Christina N; Verdun, Valerie A et al. (2014) Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling. Dev Biol 386:111-22
McCampbell, Kristen K; Wingert, Rebecca A (2014) New tides: using zebrafish to study renal regeneration. Transl Res 163:109-22
Kroeger Jr, Paul T; Wingert, Rebecca A (2014) Using zebrafish to study podocyte genesis during kidney development and regeneration. Genesis 52:771-92

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