Chronic kidney disease is a major public health concern in the US and worldwide. Myosin 1e (Myo1e), an actin-dependent motor protein expressed in glomerular visceral epithelial cells (podocytes), is necessary for normal glomerular filtration in humans and mice. Myo1e is one of the components of the slit diaphragms, protein complexes that connect adjacent podocytes and play a key role in selective protein filtration in the glomerulus. Inactivating mutations in Myo1e are associated with focal segmental glomerulosclerosis (FSGS), one of the leading causes of end stage renal disease. In this proposal, we will determine how actin-dependent motor activity of Myo1e contributes to the maintenance of normal glomerular architecture and functions. We hypothesize that Myo1e is necessary for podocyte adaptation to the changes in their environment, including changes caused by high blood pressure and other pathological conditions, via its role in regulating membrane tension and slit diaphragm stability. In this application, we propose to study the role of Myo1e in tension generation and slit diaphragm turnover using innovative biophysical and cell biological approaches.
In Aim 1, we will determine how Myo1e-mediated tension regulates podocyte activity and allows podocytes to adapt to the changing environment within the glomerulus under normal and pathological conditions.
In Aim 2, we will dissect Myo1e role in regulating slit diaphragm assembly and turnover.
In Aim 3, we will analyze the mechanisms responsible for regulation of Myo1e expression and activity. These studies will help determine how mutations in Myo1e contribute to development of FSGS and provide better understanding of the regulation of podocyte structure and function.

Public Health Relevance

Chronic kidney disease is a serious public health concern, often leading to end stage renal disease and a need for dialysis or renal transplantation. Understanding what factors cause kidney dysfunction and determine progression to end stage renal disease is important in order to prevent, diagnose, and treat chronic kidney disease. In this project, we will investigate the role of a particular protein expressed in the kidney, called myosin 1e, in normal renal functions and in kidney adaptation to pathological conditions, such as hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083345-10
Application #
10003216
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Sadusky, Anna Burkart
Project Start
2011-09-15
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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) Myosin 1e is a component of the invadosome core that contributes to regulation of invadosome dynamics. Exp Cell Res 322:265-76
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

Showing the most recent 10 out of 13 publications