In order to improve prevention and treatment of chronic kidney disease, a major public health concern in the US and worldwide, it is essential to identify proteins that are necessary for normal glomerular functions. Identification of proteins that are critical for glomerular filtration will help pinpoint molecular targets of disease pathways that lead to renal dysfunction. The goal of this research project is to identify the roles of an actin-dependent molecular motor myosin 1e (myo1e) in normal kidney functions and in development of kidney disease. Myosin 1e is expressed in glomerular podocytes, specialized kidney epithelial cells that play a critical role in selective renal filtration. We have found that myo1e knockout mice are viable but exhibit severe defects in glomerular filtration and organization. This project focuses on identification of the intracellular functions of myo1e in podocytes and analysis of the role of myo1e in maintaining normal renal filtration. These studies will help determine how changes in myo1e activity may contribute to progression of kidney disease. We propose a hypothesis that myo1e motor activity is required for its role in normal podocyte functions. In order to test this hypothesis, we will pursue the following specific aims.
Aim 1. Analyze the effects of mutations in myo1e on its functions in podocytes. In this aim we will determine the role of myo1e motor activity in regulation of podocyte migration and cell shape.
Aim 2. Determine how intracellular signaling pathways in podocytes are affected by the loss of myo1e activity and analyze regulation of myo1e motor functions by podocyte signaling.
Aim 3. Test the ability of myo1e mutants to rescue the defects in glomerular filtration in mice lacking myo1e.

Public Health Relevance

Currently more than 20 million adults in the US suffer from chronic kidney disease, which is typically caused by pathological changes in the glomerulus, the primary filtration unit in the kidney. This project is aimed at deciphering molecular mechanisms that link the loss of glomerular protein myosin 1e to the development of kidney disease. Identification of the role of myosin 1e in kidney disease may lead to the development of new therapies for kidney disease in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083345-03
Application #
8517103
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2011-09-15
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$335,819
Indirect Cost
$124,883
Name
Upstate Medical University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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Ouderkirk, Jessica L; Krendel, Mira (2014) Non-muscle myosins in tumor progression, cancer cell invasion, and metastasis. Cytoskeleton (Hoboken) 71:447-63
Ouderkirk, Jessica L; Krendel, Mira (2014) Myosin 1e is a component of the invadosome core that contributes to regulation of invadosome dynamics. Exp Cell Res 322:265-76
Zheng, Huimei; Bi, Jing; Krendel, Mira et al. (2014) Converting a binding protein into a biosensing conformational switch using protein fragment exchange. Biochemistry 53:5505-14
Bi, Jing; Pellenz, Christopher D; Krendel, Mira (2014) Visualization of cytoskeletal dynamics in podocytes using adenoviral vectors. Cytoskeleton (Hoboken) 71:145-56