BIOMED PhD Research Proposal

Title: 
Examining the Role of Chemokine Inhibition in Renal Tubulointerstitial Disease

Speaker:
Joshua Gale,  PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisors:
Maria P Martinez-Cantarin, MD
Associate Professor
Division of Nephrology 
Medical Director, Kidney and Pancreas Transplantation 
Director, Diabetes Research in ESRD and Transplant
Sidney Kimmel Medical College
Thomas Jefferson University

Fred Allen, PhD
Teaching Professor 
Associate Dean for Undergraduate Education
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
Renal tubulointerstitial disease (TID) encompasses a range of disorders that damage the kidney tubules and interstitium, leading to inflammation, fibrosis, and ultimately chronic kidney disease (CKD)—a global health crisis causing over 1.1 million deaths annually. A primary driver of this fibrotic progression is persistent macrophage infiltration, which is significantly mediated by the CX3CL1/CX3CR1 signaling axis. However, the specific therapeutic potential of CX3CR1 inhibition in TIDs, particularly when validated using dependable renal functionality measurements like measured GFR, remains to be fully understood. Our central hypothesis is that CX3CR1 inhibition will block macrophage recruitment, thereby reducing inflammation, limiting fibrosis, and preserving renal function.

To test this hypothesis, this research will first examine changes in kidney function and fibrosis following CX3CR1 inhibition across three distinct and clinically relevant models of tubulointerstitial disease: Folic acid, Oxalate, and Adenine. Primary outcomes will include measured glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine, comprehensive histopathology (trichrome, collagen III), macrophage infiltration (F4/80), and key fibrotic/inflammatory markers (Western blot/qPCR). Following this broad validation, we will utilize the most CKD-consistent model to further investigate how CX3CR1 inhibition specifically alters macrophage subsets (infiltrating vs. resident) and the accumulation of crystals. Our secondary aim will employ flow cytometry, RNA profiling, polarized light microscopy for crystal quantification, and functional assays to assess macrophage phenotype and activity.

We expect that CX3CR1 inhibition will not only improve renal function and reduce fibrosis scores but will also specifically modulate Ly6Chi infiltrating macrophages and decrease the accumulation of CaOx crystals. The expected outcomes of this research will help establish CX3CR1 as a critical therapeutic target in CKD driven by TID. This work will provide the first evidence that CX3CR1 signaling drives inflammation, reduces fibrotic activity, indirectly regulates crystal accumulation, and alters the homing of specific macrophage phenotypes. By uncovering a previously unrecognized role for macrophage subsets in crystal handling, these studies will also help reshape our understanding of the CX3CL1/CX3CR1 axis in kidney disease and provide essential mechanistic insights to guide the development of novel anti-fibrotic and anti-crystalline therapies.

The School of Biomedical Engineering, Science and Health Systems is pleased to announce its 7th Annual Immune Modulation & Engineering Symposium (IMES).