Urology

Pediatric Urology Laboratory

The Pediatric Urology Research Laboratory (PURL) at Texas Children’s Hospital and Baylor College of Medicine is co-directed by Dr. Paul Austin, MD and Dr. Scott Manson, PhD. The mission of this laboratory is to conduct novel basic science, translational, and clinical research designed to improve the treatment of disorders of the kidneys and urinary tract in children.

The PURL also serves as a robust foundation for stimulating pediatric urology research by (1) providing basic science training to fellows, graduate students, and other trainees, (2) building collaborations between scientists and urologists to promote translational and clinical research, (3) functioning as a state-of-the-art biomedical research core to support studies of urinary and renal pathophysiology in mouse models, and (4) maintaining a sample biorepository and bioinformatics database to advance pediatric urology research both at TCH/BCM and in the broader research community.

Investigators in the PURL have sustained a consistent track record of research productivity with numerous publications in leading urology, nephrology, and basic science journals. This research excellence has been recognized by being awarded the Basic Science Research Prize from the Society for Pediatric Urology and American Academy of Pediatrics four times (and nominated as a finalist three additional times). Furthermore, the PURL is one of only several pediatric urology laboratories across the country to have achieved R01-level funding from the National Institutes of Health. PURL investigators have also received the Duckett Award for Pediatric Urology Research Excellence and Research Scholar Award from the American Urological Association the Research Fellowship Award and Young Investigator’s Award from the National Kidney Foundation, and other prestigious research awards. 

Basic Science and Translational Research Projects in the PURL

Research in the PURL spans diverse areas of pediatric urology and includes the following ongoing projects:

Obstructive Uropathy and Kidney Repair. Obstructive uropathy is a leading cause of pediatric kidney disease. While the kidneys have a remarkable capacity for repairing injuries due to transient hydronephrosis, prolonged urinary obstruction results in irreversible renal injury. We have developed novel mouse models to elucidate the molecular mechanisms underlying these differential responses. These studies identified BMP7 as a key therapeutic target for stimulating kidney repair. Ongoing projects aim to identify biomarkers capable of assessing the regenerative capacity of the kidneys and the need for surgery in patients with hydronephrosis.

Manson SR, Niederhoff RA, Hruska KA, Austin PF. The BMP-7-Smad1/5/8 pathway promotes the repair of the kidney after obstruction-induced renal injury. The Journal of Urology 185: 2523-30 (2011).
Manson SR, Niederhoff RA, Hruska KA, Austin PF. Endogenous BMP-7 is a critical molecular determinant of the reversibility of obstruction-induced renal injuries. American Journal of Physiology- Renal Physiology 301(6): F1293-302 (2011). 
Manson SR, Song JB, Hruska KA, Liapis HT, Austin PF. The loss of Bmp-7 expression contributes to the progression of kidney disease in patients with obstructive uropathies. The Journal of Urology 193 (5 Suppl): 1860-9 (2015).
Manson SR, Austin PF, Guo Q, Moore KH. The critical roles of BMP-7 in kidney development, the responses to renal injury, and chronic kidney disease. Vitamins and Hormones 99: 91-144 (2015).

Obstructive Uropathy and Renal Fibrosis. The onset of renal fibrosis drives disease progression in the obstructed kidney. This dysregulated wound healing response largely results from widespread changes in gene transcription. Recent work in our lab identified HDAC transcription factors as key regulators of gene transcription in renal fibrosis and promising targets for the development of anti-fibrotic therapies. Ongoing projects aim to define the transcriptional networks controlling the differentiation of myofibroblasts from mesenchymal stem cells in renal fibrosis.  

Manson SR, Hruska KA, Austin PF. The HDAC-dependent suppression of Bmp-7 transcription contributes to the pathogenesis of renal injury in obstructive uropathies. The Journal of Urology 191(1): 242-52 (2014). 
Manson SR, Guo Q, Moore KH, Austin PF. Epigenetic regulation by HDAC proteins plays a critical role in the progression of renal fibrosis. Pediatric Nephrology 30: 1543 (2015).  
Singh S, Manson SR, Lee H, Kim Y, Liu T, Guo Q, Geminiani JJ, Austin PF, Chen YM. Tubular overexpression of angiopoietin-1 attenuates renal fibrosis. PLOS One 11(7): e0158908 (2016)
Manson SR, Guo Q, Moore H, Molina CA, Geminiani JJ, Vricella GG, Koenig JH, Leopold ZR, Fain ME, Song JB, Liapis H, Austin PF. HDAC8 plays a critical role in myofibroblast activation and the progression fibrosis. Kidney International (in submission). 

Obstructive Uropathy and Kidney Development. A critical limitation in the study of obstructive uropathy has been the reliance upon models which examine disease progression in the mature kidney. We have developed novel mouse models of congenital urinary obstruction to study disease progression during key stages of kidney development. These studies showed that developmental context has a significant impact on the mechanisms of disease progression, treatment strategies, long-term susceptibility to kidney disease, and the need for intervention. Ongoing projects are evaluating promising therapeutic targets for preventing impaired nephrogenesis and proliferative growth following urinary obstruction in the developing kidney.

Manson SR, Geminiani JJ, Vricella GJ, Guo Q, Moore KH, Austin PF. Developmental context has a significant impact on disease progression in the obstructed kidney and potential treatment strategies. Pediatric Nephrology 30: 1555-6 (2015).
Manson SR, Geminiani JJ, Vricella GJ, Molina CA, Guo Q, Moore KH, Leopold ZR, Fain ME, Austin PF. Injury to the developing kidney leads to impaired maturation but not inflammation or fibrosis. Journal of the American Society of Nephrology (in submission).
Manson SR, Molina CA, Austin PF. Developmental context impacts long-term outcomes in congenital urinary obstruction. Annual Meeting of the American Urological Association, San Francisco, California, May 2018.

Acute Kidney Injury and Biomarkers. An important clinical need is biomarkers that are capable of early detection in patients at risk for acute kidney injury. In collaboration with investigators at Washington University, we have established a key role for endoplasmic reticulum stress in the pathogenesis of acute kidney injury and identified MANF and CRELD2 as effective urinary biomarkers for early detection. Ongoing studies are examining their potential utility for detecting renal injury in patients with hydronephrosis. 

Kim Y, Lee H, Manson SR, Lindahl M, Evans B, Miner JH, Urano F, Chen YM. Discovery of mesencephalic astrocyte-derived neurotrophic factor as a urine biomarker for endoplasmic reticulum stress-related kidney diseases. Journal of the American Society of Nephrology 27: 2974-82 (2016).
Kim Y, Park SJ, Manson SR, Molina CA, Kidd K, Thiessen-Philbrook H, Perry RJ, Liapis H, Kmoch S, Parikh CR, Bleyer AJ, Chen YM. Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease. Journal of Clinical Investigation Insights 2(23): 92896 (2017).

Bladder Dysfunction and Therapeutic Targets. Bladder dysfunction is a major healthcare burden and characterized by decreased storage volume, voiding dysfunction, incontinence, bladder pain, and other symptoms that adversely impact quality of life. Our research aims to elucidate the molecular mechanisms that mediate injury, inflammation, fibrosis, and other pathologic processes in the bladder. This research has established the Skp2-p27 pathway as a critical regulator of obstruction-induced bladder hyperplasia. Ongoing studies are evaluating promising therapeutic targets for inhibiting inflammation and fibrosis in the bladder.

Jiang X, Austin PF, Niederhoff RA, Manson SR, Riehm JJ, Cook BL, Pengue G, Chitaley K, Nakayama K, Nakayama KI, Weintraub SJ. Mechanoregulation of proliferation. Molecular and Cellular Biology 29(18): 5104-14 (2009).
Niederhoff RA, Manson SR, Tawfik A, Austin PF. The physiological significance of p27(KIP1) expression in detrusor function. The Journal of Urology 184(4 Suppl): 1686-91 (2010).
Molina CA, Manson SR, Austin PF. Defining the core mechanisms in overactive bladder by applying integrative transcriptomics. Annual Meeting of the American Urological Association, San Francisco, California, May 2018.

Stone Disease and Crystal-Cell Adhesion. Therapeutic options for stone disease are limited, in large part because the early events in stone formation remain poorly defined. We have developed novel biochemical strategies to study the adhesion of urinary crystals to the surface of renal epithelial cells during stone formation. Using these techniques, we established a key role for urinary proteins in inhibiting crystal-cell adhesion. We then used proteomics to identify 48 crystal-binding proteins in urine samples from patients. Ongoing studies are evaluating their potential utility as novel therapies and biomarkers in stone disease.  

Manson SR, Koenig JF, Guo Q, Moore KH, Austin PF. Identification of calcium-oxalate binding proteins in human urine that prevent crystal adhesion in an in vitro model of kidney stone formation. Annual Meeting of the American Society of Nephrology, San Diego, California, November 2015.
Manson SR, Koenig JF, Guo Q, Moore KH, Leopold ZR, Austin PF. Identification of calcium-oxalate binding proteins in human urine that prevent crystal adhesion in an in vitro model of kidney stone formation. American Journal of Physiology- Renal Physiology (in submission).
Koenig JF, Manson SR, Guo Q, Moore KH, Leopold Z, Austin PF. Identification of putative urinary biomarkers for pediatric stone disease by combining molecular, biochemical, and proteomic approaches. Fall Meeting of the Society for Pediatric Urology, Dallas, Texas, September, 2016.

Congenital Genitourinary Defects and Genomics. A wide range of genitourinary defects are encountered in children. A key step in improving the diagnosis and treatment of these conditions is defining their genetic basis. In projects led by Dr. Abhishek Seth, comparative genomic hybridization microarrays are being used to improve the diagnosis of chromosomal defects in children with congenital genitourinary defects including ureteropelvic junction obstruction, vesicoureteral reflux, cryptorchidism, hypospadias, and other conditions.


Urologic Disorders and Transcriptomics. A critical barrier in pediatric urology research is the limited amount of funding available for basic science research. 

To minimize the impact of this barrier, we are developing an internet-based pediatric urology bioinformatics database to accelerate the development and initial testing of research hypotheses. We have generated whole transcriptome mRNA expression (>15k genes) datasets of from six commonly studied mouse models of urologic disorders. This will be a long-term initiative in the PURL and be expanded over time to include datasets from additional mouse models, human disease, and other techniques for high-throughput bioinformatic analysis.   

Molina CA, Manson SR, Austin PF. Defining the core mechanisms in overactive bladder by applying integrative transcriptomics. Annual Meeting of the American Urological Association, San Francisco, California, May 2018.

Pediatric Device Innovation in Pediatric Urology. Supporting the development of innovative medical devices is fundamental to advancing the treatment of urologic disorders. This objective is particularly important in pediatrics, where the development of medical devices is subject to unique challenges and a considerably slower rate of innovation than with adult medical devices. In projects led by Dr. Chester Koh, a variety of novel medical devices are being developed through collaborations with the engineering schools at Rice University and Texas A&M University as well as local device development firms.

Grant M, Stanasel I, and Koh CJ.  Pediatric Medical Device Consortia – A Novel Pathway for Device Development for Pediatric Urologists and other Pediatric Specialists.  Urology Practice, 2015 Aug, 2(4): 206 – 210.
Sack B, Elizondo RA, Huang GO, Janzen N, Espinoza J, Sanz-Cortes M, Dietrich JE, Hakim J, Richardson E, Oden M, Hanks J, Haridas B, Hury JF, and Koh CJ.  Pediatric Medical Device Development by Surgeons via Capstone Engineering Design Programs.  J Pediatr Surg. 2017 Feb 6. pii: S0022-3468(17)30100-8. doi: 10.1016/j.jpedsurg.2017.01.067. [Epub ahead of print]

Grants and databases

CDC
9/1/2014 – 8/31/2019
1U01DD001072-01 - Component B – “Texas Children's Hospital and Baylor College of Medicine Spina Bifida Registry”
1U01DD001070-01 - Component C - “Urologic Management for Young Children with Spina Bifida at TCH/BCM”
PI: H. Castillo, J. Castillo, Koh

The Auxiliary to Texas Children’s Hospital
8/2014 – present
Denton Cooley Innovation Award
PI: Koh

1P50FD004896-01
9/16/2013 – 8/31/2018
FDA P50 Pediatric Medical Device Consortia Grants
“Southern California Center for Technology and Innovation in Pediatrics (CTIP)”
Multi-PI: Koh

K12DK083014-06
NIH/NIDDK
Multidisciplinary K12 Urologic Research (KURe) Career Development Program
PI: Lamb
Recipient: Seth

Department of Surgery Seed Grant, Texas Children’s Hospital
12/2013 – 6/2015
“Identification of Urinary Inflammation-Specific DNA Methylation Markers to Aid in Early Prediction of Severe Hemorrhagic Cystitis”
PI: Seth

Department of Surgery Seed Grant, Texas Children’s Hospital
12/2013 – 6/2015
“Minimizing VCUG Discomfort with Neuromodulation”
PI: Janzen

Watson Laboratories, Inc.
12/2013 – present
“A Multi-Center, Double-Blind, Placebo-Controlled, Dose-Titration Study Evaluating the Efficacy, Safety, Pharmacodynamics of Oxybutynin Chloride Topical Gel for the Treatment of Detrusor Overactivity Associated with a Neurological Condition in Pediatric Subjects - Protocol OG09002 (Multi-Institutional)”
PI: Koh

Allergan
4/2014 – present
“BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor Overactivity in Patients 8 to 17 Years of Age - Protocol 191622-120 (Multi-Institutional)”
PI: Koh

NIH/NIDDK
8/2007 - 7/2012
"Improving diagnosis of congenital genitourinary abnormalities"
PI: Dolores Lamb

Pfizer
1/2015 - present
"A 24-week randomized, open-label study to evaluate the safety and efficacy of Festerodine in subjects 6 -17 years with symptoms of detrusor overactivity associated with a neurological condition"
PI: Koh

2016 American Urological Association Data Grants Award
11/2015 - present
"Feasibility of establishing an EMR-based multicenter research network to assess adherence to AUA vesicoureteral reflux guidelines"
Co-I: Janzen

DOS Seed Grant 
Awarded spring 2017
"Ureteral stent electromagnetic removal (USER) device for pediatric patients"
PI: Koh

NIH SBIR-BCM sub-recipient NIH/NIDDK
9/2017 - 8/2018
"Ureteral stent electromagnetic removal (USER) device for pediatric patients"
PI: Varadhachary/Koh (co-PI)/Richardson

2017 Research SPU Grant
Awarded 2017
"The role of KCTD123 in genitourinary tract development"
PI: Seth

NIH R01 
7/13 - 4/18
"Short-term outcomes of interventions for reproductive dysfunction"
PI: Wisniewishi and co-I:Austin

Allergan
12/13 - 12/17
"BOTOX in the treatment of urinary incontinence due to neurogenic detrusor overactivity in patients 8 -17 years of age"
PI: Austin