This K23 application is submitted by Angie C. Jelin, MD, Assistant Professor of Gynecology and Obstetrics/Genetics at the Johns Hopkins School of Medicine. Dr. Jelin?s long term goal is to become an independent investigator in fetal urinary tract anomalies. Towards this goal, she proposes a mentored career development plan that provides training in whole genome sequencing (WGS), genomics, CRISPR/Cas9, and mouse phenotyping. Urogenital anomalies account for 20-30% of prenatally detected structural defects. Bladder Exstrophy Epispadias Complex (BEEC) describes a subset of anomalies with a spectrum of developmental defects ranging from a mild form of epispadias, to classic bladder exstrophy, to omphalocele, exstrophy, imperforate anus, spinal anomalies (OEIS) complex. Patients with BEEC suffer substantial morbidity and mortality due to impaired genito-urinary dysfunction. The etiology of BEEC is largely unknown. Elucidating the underlying genetic component is critical to gaining a better understanding of the developmental signaling pathways and is likely the first step to developing targeted therapy. Variants in genes identified in other urogenital anomalies appear to be responsible for some cases of BEEC including IS, WNT3, WNT9b, PLAG1 and p63. We propose to take advantage of our extensive analytical experience in the Baylor Hopkins Center for Mendelian Genomics and perform WGS on parent-proband trios for whom the proband has BEEC. One study utilizing whole exome sequencing (WES), identified candidate genes (SLC20A1 and CELSR3) in 2 out of 8 affected patients, providing reassurance that our proposed strategy will be successful. Following WGS, we will explore the pathogenicity of genetic variants by employing a knockout mouse model using CRISPR/Cas9 technology via collaboration with the Jackson Laboratory. Final validation will include mouse phenotyping by dynamic contrast-enhanced MRI under the expertise of, Cory Brayton, mouse pathologist.
Aim 1. To identify the genetic basis of BEEC through Whole Genome Sequencing (WGS) Aim 2a. To create the founder (F0) homozygous knockout mouse using CRISPR/Cas9.
Aim 2 b. To define the murine model phenotype using dynamic contrast enhanced MRI.

Public Health Relevance

Patients with Bladder Exstrophy Epispadias Complex suffer substantial morbidity and mortality due to impaired genito-urinary dysfunction. The etiology of BEEC is largely unknown. Elucidating the underlying genetic component is critical to gaining a better understanding of the developmental signaling pathways and is likely the first step to developing targeted therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK119949-03
Application #
10115031
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2019-05-10
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218