The overarching goal of the proposed work is to better understand the role of Kim-1 mediated phagocytosis in kidney injury. The long term goal is to identify potential regulatory mechanisms mediated by Kim-1 which could be used as targets to ameliorate kidney injury. Specifically, we will use in vitro and in vivo techniques to delineate the mechanism by which Kim-1 regulates autophagy and the effect Kim-1 mediated autophagy has on MHC class II presentation. In our first specific aim, the goal is to identify the mechanism by which Kim-1 upregulates autophagy and targets phagocytosed material to the autophagosome. Using chemical and genetic methods we will examine the trafficking of Kim-1 positive phagosomes to the autophagosome. We will also determine whether the cytoplasmic tail of Kim-1 targets phagocytosed debris to the autophagosome. Finally, we will examine whether Kim-1 cytoplasmic tail targets the phagosome to the autophagosome. In the second specific aim, we will examine whether Kim-1 induced autophagy leads to MHC class II presentation of peptides from the phagocytosed debris. We will approach this using two models cells not expressing Kim-1, expressing Kim-1 or expressing a phagocytosis null mutant and wt mice or mice expressing a phagocytosis null Kim- 1. First, we will co-localize Kim-1 with the autophagosome and MHC antigen processing compartment in cell culture and injured kidneys. We will then compare the presentation of peptides on MHC class II, following exposure to phagocytic targets. Finally, we will examine whether autophagy is necessary for Kim-1 expressing tubule cells to activate T-cells following phagocytosis. Relevance: Acute kidney injury remains a major kidney disease associated with high morbidity and mortality. The incidence of AKI has been steadily increasing over the past decade and is expected to increase further. The mortality rate of patients diagnosed with kidney failure is often 30-50%. Although research has lead to many treatment options and increased survivability, more research is needed to find a solution to this problem. Our study is aimed at better understanding the function of a protein (Kim-1) which is found associated with most forms of kidney failure. We will determine whether Kim-1 contributes to the autophagy and MHC presentation observed in kidney injury as well as identify potential targets for therapeutic intervention.

Public Health Relevance

Acute kidney injury remains a major kidney disease associated with high morbidity and mortality. The incidence of AKI has been steadily increasing over the past decade and is expected to increase further. The mortality rate of patients diagnosed with kidney failure is often 30-50%. Although research has lead to many treatment options and increased survivability, more research is needed to find a solution to this problem. Our study is aimed at better understanding the function of a protein (Kim-1) which is found associated with most forms of kidney failure. We will determine how Kim-1 regulates autophagy and whether this autophagy contributes to the inflammation observed in kidney injury as well as identifies potential targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK088418-03
Application #
8290478
Study Section
Special Emphasis Panel (ZDK1-GRB-G (J1))
Program Officer
Rankin, Tracy L
Project Start
2010-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$53,942
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115