Targeting the C5a-C5aR1 signaling axis in diabetic nephropathy - JDRF Advanced Postdoctoral Fellowship

  • Tan, Min (Primary Chief Investigator (PCI))

Project: Research

Project Details

Project Description

Diabetic nephropathy remains a major complication of diabetes despite intensive glycemic control and the use of antihypertensive drugs. Thus, identification of new molecular targets to retard, stop and/or reverse some, if not all, of diabetic nephropathy would address a major area of unmet clinical need.
HYPOTHESIS: Complement pathways, specifically the C5a-C5aR1 signaling axis, are activated in Type 1 diabetes and this activation contributes to tissue injury and inflammation associated with DN. Thus, inhibition of C5a-C5aR1 signaling will ameliorate the development and progression of diabetic nephropathy.
A. Specific Aims
Aim 1: To characterize the classical, lectin, alternate and extrinsic complement pathways in the kidney in a mouse model of T1D (Ins2-Akita mouse).
Aim 2: To assess the deposition of complement activation products within the human kidney, circulation and urine of patients with diabetes and varying degrees of renal function.
Aim 3: To validate that blockade of the C5a receptor (C5aR1), by (a) genetic deletion using C5aR-/- mice, and (b) use of the C5aR1 antagonist PMX-53 in a preclinical model of T1D is renoprotective.
Effective start/end date1/01/1730/04/20