2012 NephCure Award Recipients
NephCure Foundation Post-Doctoral Fellowship Grant
Ehtesham Arif, Ph.D.
University of Pennsylvania
The role of Myo1c in maintaining the glomerular filtration function
Scientific investigations have demonstrated that the dynamic changes in podocyte proteins Neph1 and Nephrin govern the loss of cell function leading to proteinuria and kidney damage. Dr. Arif identified recently a new motor protein called Myo1c that may regulate the localization of Neph1 and Nephrin in podocytes. His NephCure funded research project uses mice and zebrafish models to investigate the dynamic interactions between Myo1c, Neph1 and Nephrin and decipher the role of Myo1c in the maintenance of glomerular structure and function. An understanding of the functional significance of Myo1c may aid in identifying novel therapeutic targets for the treatment of glomerular diseases.
NephCure Young Investigator Career Development Award
Hua A. (Jenny) Lu, M.D., Ph.D.
Massachusetts General Hospital
Study of a novel gene, FAM49B, on the pathogenesis of proteinuric glomerular disease
Fam49B is a protein that does not belong to the usual set of proteins associated with proteinuria and Nephrotic Syndrome. Dr. Lu’s research seeks to categorize its function and molecular mechanism using zebra fish and mouse models. Fam49B is highly expressed in developing and mature podocytes in the kidneys of both of these animal models. In previous studies, Dr. Lu demonstrated how knocking down Fam49B in zebra fish embryos led to podocyte foot process effacement, altered podocyte morphology and renal failure. A reduction of Fam49B expression has also been observed in kidneys from patients with FSGS. Her research will investigate the function of Fam49B in podocyte biology and pathophysiology in vitro (lab cultures) and in vivo (animal models) and will examine the mechanism by which Fam49B regulates the structure and function of the podocyte through modulating phospholipids metabolism, protein/vesicular trafficking and cell signaling.
NephCure Foundation- ASN Foundation for Kidney Research Grant
Michelle Denburg, M.D.
The Children’s Hospital of Philadelphia
Defining Vitamin D Status in the Nephrotic Patient
Dr. Denburg is an investigator in pediatric nephrology with advanced training in clinical epidemiology and a research focus on Vitamin D metabolism in proteinuric patients. Abnormal Vitamin D metabolism is an important complication of Nephrotic Syndrome in both adults and children. Vitamin D can be lost in the urine among the proteins that are spilled, and there is evidence that the kidney may handle Vitamin D inappropriately when dealing with the complications of a disease relapse. Vitamin D deficiency is known to cause problems with bone health, but there is also evidence that Vitamin D deficiency can worsen kidney scarring, the most serious concern in Nephrotic Syndrome. Dr. Denburg’s study has two major goals. The first is to expand her preliminary data set by measuring Vitamin D levels of patients with biopsy proven NS enrolled in the NEPTUNE study. The second is to study how different levels of administration of Vitamin D optimize bone health and minimize kidney scarring.
The Kidney Foundation of Canada-NephCure Foundation Research Grant
York Pei, M.D.
University of Toronto, Toronto, Canada
Molecular genetics of idiopathic nephrotic syndrome
The goal of Dr. Pei’s research is to identify the causative factors for steroid sensitive (SS) and steroid resistant (SR) NS using a genetic approach and studying families with more than one member who has primary NS. Recent documentation of genes in families with members who have both SS-minimal change disease and SS-FSGS suggest that this is a rare recessive genetic disorder. Dr. Pei’s hypothesis is that there are different pathogenic pathways for SR- and SS FSGS that run in families, and that these are associated with different molecular mechanisms within the circulating T-cells and glomerular podocytes, respectively. SR-FSGS has been demonstrated to be associated with mutations of certain podocyte-specific proteins (NPHS2, ACTN4, CD2AP, TRPC6, PLCE1, INF2, and MYO1E), but the relationship of this familial syndrome to cases of SS-MCD/FSGS is still unclear. This grant will support three main aims: 1) to expand patient resources by collecting additional families with two or more individuals affected with SS-MCD/FSGS or SR-FSGS; 2) to identify disease genes for familial SS-MCD/FSGS by performing exome sequencing on selected patients from the study families focusing on specific ROH tracts of interest; and 3) to identify disease genes for familial SR-FSGS by performing genome-wide linkage scan and exome sequencing on selected patients. Clinical management of FSGS is currently limited by a gap of knowledge on the pathobiology of this heterogeneous collection of disorders. By identifying underlying genetic factors, Dr. Pei’s study has the potential to provide a foundation for developing better diagnostic tests and targeted therapies for both SS- and SR-FSGS.
Agnieszka Swiatecka-Urban, M.D.
University of Pittsburgh, Pittsburgh, PA
Dynamic regulation of the slit diaphragm integrity by nephrin endocytosis
The membrane structure localized at the junction of podocytes, called the slit diaphragm, is a major component of the kidney’s filtration barrier and an extremely complex structure that undergoes constant change. Research has identified several elements that build this structure, but it remains largely unknown how the building blocks interconnect. Dr. Swiatecka-Urban’s research seeks to understand the mechanisms that control how the slit diaphragm-associated protein nephrin is trafficked in and out of the cell and how changes in the abundance of nephrin can control the integrity of the slit diaphragm. (The process by which a cell absorbs molecules outside the cell and brings them inside is called endocytosis.) Understanding these mechanisms may lead to new therapeutic approaches to correct the defective nephrin expression seen in patients with FSGS and Minimal Change Disease.