Recent studies in recurrent FSGS (rFSGS) suggest a potential role for CD40 auto- antibody (autoAb) isolated from the sera of FSGS patients. Most interestingly, CD40 autoAb and soluble urokinase receptor (suPAR) together drive the development of nephropathy in rodents, while neither one could not do it alone sufficiently. We hypothesize that CD40 autoAb plays an important role in rFSGS either as a biomarker or as an injury factor contributing to rFSGS, and that CD40 autoAb and suPAR synergistically induce FSGS. Blocking CD40 or suPAR-?v?3 integrin signaling could represent novel therapeutic concepts for FSGS. Thus in this research program, we propose a highly innovative and translational study with three independent but cohesive Aims to explore the mechanisms of suPAR and CD40 autoAb interaction that cause renal damages.
In Aim 1, we will assess the implication of CD40 and CD40 autoAb in FSGS.
In Aim 2, we explore whether and how suPAR and CD40 autoAb induce FSGS in animal models in vivo.
In Aim 3, we will test the therapeutic concepts by blocking suPAR induced podocyte ?3 integrin activity and/or by interfering CD40 related signaling. In sum, this research program will help unravel the pathogenesis of FSGS recurrence and develop novel targeted therapeutic strategies for FSGS as well. The study combines unique expertise of domain experts in nephrology, immunology and podocyte biology, with deliverables of high clinical impact and immediate translation to the bedside.

Public Health Relevance

Focal segmental glomerulosclerosis (FSGS) is an important cause of kidney failure in adults and children requiring kidney transplantation, but is associated with a high rate of recurrence of the original disease with rapid loss of the organ. We will evaluate the role of naturally occurring factors such as autoantibodies to Cd40 and suPAR, in the pathogenesis of FSGS disease and explore novel therapeutic options to abrogate this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK109720-03
Application #
9668947
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Abbott, Kevin C
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118