Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083345-04
Application #
8675846
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
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Upstate Medical University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Syracuse
State
NY
Country
United States
Zip Code
13210

  Publications

Heim, Joel B; Squirewell, Edwin J; Neu, Ancilla et al. (2017) Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix. Proc Natl Acad Sci U S A 114:3933-3938
Goreczny, G J; Ouderkirk-Pecone, J L; Olson, E C et al. (2017) Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene 36:2693-2703
Ouderkirk-Pecone, Jessica L; Goreczny, Gregory J; Chase, Sharon E et al. (2016) Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation. Oncotarget 7:46419-46432
Randles, Michael J; Collinson, Sophie; Starborg, Tobias et al. (2016) Three-dimensional electron microscopy reveals the evolution of glomerular barrier injury. Sci Rep 6:35068
Bi, Jing; Carroll, Robert T; James, Michael L et al. (2015) Effects of FSGS-associated mutations on the stability and function of myosin-1 in fission yeast. Dis Model Mech 8:891-902
Wenzel, Jens; Ouderkirk, Jessica L; Krendel, Mira et al. (2015) Class I myosin Myo1e regulates TLR4-triggered macrophage spreading, chemokine release, and antigen presentation via MHC class II. Eur J Immunol 45:225-37
Ouderkirk, Jessica L; Krendel, Mira (2014) Non-muscle myosins in tumor progression, cancer cell invasion, and metastasis. Cytoskeleton (Hoboken) 71:447-63
Bi, Jing; Pellenz, Christopher D; Krendel, Mira (2014) Visualization of cytoskeletal dynamics in podocytes using adenoviral vectors. Cytoskeleton (Hoboken) 71:145-56
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
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

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