Pilot & Feasibility Program (P&F)

The Pilot and Feasibility program encourages young and established investigators to undertake research relevant to kidney development, engineering and disease multiomics to accelerate the acquisition of knowledge that can be applied to treatment of children with renal and urological diseases and engineer devices to replenish kidney function.

Providing opportunities to:

  • Attract new scientific expertise to the study of human pediatric renal physiology, kidney development and pediatric kidney disorders
  • Encourage multidisciplinary research in these areas
  • Develop the pediatric nephrology research community

The areas supported by the PCEN include kidney development, experiments using iPSCs, pediatric kidney diseases (CAKUT, glomerular diseases, AKI, CKD), tissue engineering, disease modeling, pediatric tissue-based research, multiomics studies related to single cell and spatially resolved methods to understand kidney biology. Human and non-human model system studies are eligible. Use of PCEN core services is not a requirement.

Awardees

PI Cycle Career stage Institution Title: Description:
Kyle McCracken, MD, PhD 1 Early Cincinnati Children’s Hospital Medical Center Regulation of cell fate determination in the ureteric bud lineage in hPSC-derived organoids In this project, we will use human pluripotent stem cell-derived organoids and fluorescent lineage reporters to elucidate the mechanisms that regulate cell fate decisions in the developing urinary collecting system. These pilot studies will inform our approach and ability to generate distinct types of epithelial tissues from stem cells, including the ureter and collecting duct, which will have diverse applications in kidney tissue engineering and disease modeling.
Moe R. Mahjoub, PhD 1 Established Washington University in St. Louis Characterizing centrosomal pathways underlying congenital kidney developmental defects and early-onset fibrocystic disease Congenital fibrocystic kidney “ciliopathies” comprise a group of pediatric disorders caused by mutations in genes associated with the centrosome-cilium organelle complex. There are no effective molecular therapies that successfully halt disease progression. Understanding the underlying cellular and molecular mechanisms that contribute to the disease is critical in developing an effective therapeutic strategy. The goal of this project is to identify pathways that are disrupted in the rare, early-onset pediatric renal ciliopathy diseases caused by mutations in centrosome-associated genes. These experiments will be performed using a new mouse model of pediatric ciliopathies, together with single-cell sequencing approaches.
Albert Liu, MD 1 Early Washington University in St. Louis Mechanism of hypertension in metabolic syndrome and post-transplant obesity and diabetes Metabolic syndrome is a complex constellation of obesity, insulin resistance, dyslipidemia, and hypertension. In metabolic syndrome, the hypertension is thought to be due to endothelial dysfunction as a result of the other components of metabolic syndrome. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a class of medication originally approved for type 2 diabetes mellitus with recent approval for obesity, and use of these medications have been colloquially associated with decreased need for antihypertensive medications. We aim to assess the relationship of GLP-1RA use and associated need for antihypertensive medications, and also assess vascular function using non-invasive methods (pulse wave analysis, pulse wave velocity, carotid intima-media thickness, and flow-mediated dilation) to assess vascular functioning in pediatric patients with metabolic syndrome as compared to healthy individuals, as well as assess changes in these assessments in patients with metabolic syndrome receiving GLP-1RA therapy.
Nina Mann, MD 2 Early Children’s Hospital, Boston Identification of isoform-specific WT1 interaction partners Wilms’ tumor 1, or WT1, plays an essential role in both nephrogenesis and maintenance of the adult podocytes. There are at least 36 different WT1 isoforms, with the two most common isoforms, designated WT1-KTs and +KTS differing in the presence or absence of three amino acids, lysine-threonine-serine, between the protein’s third and fourth zinc fingers. Interestingly, these two isoforms exhibit different nuclear localization patterns and DNA-binding affinity, and have been shown to have distinct yet overlapping cellular roles. Splice site variants that disrupt the ratio of the WT1-KTS and +KTS isoforms can cause progressive glomerulopathy and disorders of sexual differentiation in humans. The aims of this project are to apply proximity labeling and quantitative mass spectrometry to better understand the differential functions of the WT1-KTS and +KTS isoforms and to identify interaction partners that regulate WT1 transcriptional activity. We also aim to determine how WT1 patient variants disrupt protein-protein interactions and cause disease.
Vidhi Dalal, MD 2 Early Lurie Children’s Hospital, Chicago Role and regulation of TCF21 expression in developing podocytes Focal segmental glomerulosclerosis (FSGS) is a major cause of end stage kidney disease and is characterized by podocyte dysfunction. Our laboratory identified TCF21 as an essential transcription factor for podocyte development. Despite its central role in podocyte and glomerular health, the aspects of podocyte structure and function regulated by TCF21 are not well understood. The goal of this project is to determine how TCF21 contributes to podocyte development and homeostasis using a podocyte-specific Tcf21-knockout mouse. Furthering our understanding of podocyte biology could help us develop new insights into how this biology is disrupted in disease.
Andreas Herrlich 3 Established Washington University in St. Louis AKI-induced neuroinflammation and neurocognitive dysfunction in juvenile mice Acute kidney injury (AKI) is a common clinical problem in the adult and pediatric population. AKI morbidity and mortality mostly occurs due to remote secondary organ complications not treatable by dialysis (i.e. not caused by uremia) including acute and chronic neurocognitive dysfunction and pulmonary complications. The Herrlich Lab has identified a critical interorgan mediator released exclusively by the injured kidney that causes remote lung inflammation (Khamissi Science Advances 2022) and neurocognitive dysfunction (submitted work). Little is known about AKI-induced secondary organ complications in children, but circumstantial evidence suggests that they may also experience remote organ complications in the lung and brain. The current PCEN grant proposal by the Herrlich Lab aims to determine the impact of AKI on neuroinflammation, neurocognitive outcomes, and brain development in a pre-clinical study in juvenile mice.
Elizabeth Nguyen 3 Early Seattle Children’s Detection of hidden variants in cystic kidney disease using long-read sequencing from serum and urine This project aims to improve the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) by developing a novel approach combining long-read DNA sequencing with non-invasive urine sampling to detect genetic variants missed by conventional testing. Using this innovative method, we will analyze both known and unsolved cases of ADPKD to validate our approach and identify previously undetectable disease-causing variants in PKD1/2 genes.
Kaye Brathwaite 3 Early Washington University in St. Louis Identification of novel therapeutic targets for Alport syndrome using multi-omic investigation of podocytes Our goal is to investigate how podocytes are altered in Alport syndrome using multi-omic approaches. We aim to define transcriptional and gene regulatory changes in podocytes as a function of the glomerular basement membrane defects and the resulting mechanical stresses. We hope that our findings will potentially identify new targets for therapy for children with Alport syndrome.

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