Child Health Research Center
“Noninvasive MRI Techniques to Detect Pathology in Murine Models of Renal Disease”
Working Review of Pending NIH Proposal
Dr. Jennifer Charlton (presenting)
Assistant Professor Pediatrics
Dr. W. Gerald Teague (moderator)
Associate Director, Clinical Research, CHRC
Second floor Conference Room
Friday, September 18, 2015
Light Refreshments Served
*Please RSVP to Wendy Cline (firstname.lastname@example.org) so that she can plan accordingly
A. Specific Aims
The long-term goal of this work is to measure nephron structure and function in vivo in human kidneys in health and disease. The total number and volume of glomeruli (Nglom and Vglom) are linked to kidney function and susceptibility to renal and systemic disease. We are developing magnetic resonance imaging (MRI) techniques, using cationic ferritin enhancement (CFE-MRI), to give an unprecedented, three-dimensional, integrated view of glomerular structure and renal morphology. We propose to establish these techniques in mouse models of human chronic kidney disease (CKD), to comprehensively examine the pathologic mechanisms driving the appearance of image-based biomarkers.
SA 1: Develop cationic ferritin as a targeted contrast agent for MRI-based glomerular pathology in mouse models of kidney disease
Rationale: Genetically manipulated mouse models are important to understanding human renal disease and developing new therapies. In this proposal, mouse strains have been selected to evaluate the sensitivity and specificity of CFE-MRI, covering glomerular pathologies analogous to what is observed in humans: glomerular hypertrophy, and glomerular basement membrane changes leading to CKD. We will examine two models: 1) Os/+ for isolated nephron reduction and glomerular hypertrophy and 2) overexpression of TGF-β1 for progressive changes in the glomerular basement membrane. We will determine the relationship between histopathology and MRI findings predicting to glomerular microstructural changes with CKD.
1.1. Measure Nglom and Vglom with CFE-MRI in healthy and diseased mice
1.2. Determine the temporal changes of MRI biomarkers of glomerular microstructural pathology with progression of renal disease in the mouse
1.3. Measure toxicity and biodistribution of horse and mouse recombinant CF in healthy and diseased mice.
Hypotheses: (i) CFE-MRI can be used to accurately measure glomerular number and size in healthy mice and those with progressive nephropathy, (ii) Microstructural markers detected by MRI-based virtual histopathology can predict the development of glomerular damage associated with CKD (iii) CF can be nontoxic in MRI-detectable doses in mouse models of renal disease.
SA 2: Develop MRI techniques to measure vascular microstructure in mouse models of kidney disease
Rationale: Vascular hypertrophy and sclerosis are common histologic observations in CKD, coincident with and possibly preceding glomerular damage. Susceptibility-weighted MRI techniques can be used to map the microvasculature of the mouse kidney, giving a 3D view of vascular diameter, density, distribution, and perfusion. Here we will develop novel MRI techniques to examine and quantify the development of vascular damage in the eNOS-/- mouse, as a model for vascular anomalies developing CKD.
2.1. Noninvasively measure and quantitate vascular diameter in the healthy mouse kidney.
2.2. Determine the effects of vascular remodeling on apparent vessel diameter in the eNOS-/- mouse.
Hypotheses: i) 3D MRI can be used to accurately measure and map vascular diameter and density in healthy mice and ii) Microvascular pathology can be detected in eNOS-/- mice with abnormal vascular development.
SA 3: Develop MRI markers of tubulointerstitial pathology in mouse models of kidney disease
Rationale: The loss of nephron mass and filtration are the basis for loss of renal function in CKD. This loss is followed by development of interstitial and tubular fibrosis. There are currently no techniques to detect early microstructural changes associated with nephron loss and fibrosis. Here we propose and validate an MRI technique based on non-Gaussian diffusion-weighted MRI (DWI) that is sensitive to tissue water compartmentation and renal cortical and medullary interstitial damage. We apply this technique to investigate the folate toxicity model of interstitial fibrosis, and compare the results to site-specific histology.
3.1. Noninvasively measure and quantitate vascular diameter in the healthy mouse kidney.
3.2. Quantitate the effects of folate toxicity on water compartmentalization in the mouse.
Hypothesis: Diffusion-weighted MRI can accurately detect early microstructural tubulointerstitial damage associated with nephron loss and tubulointerstitial fibrosis.
The selected mouse models have unique and specific features of human renal disease. We have designed this proposal to use these cleaner mouse models to deconstruct the heterogeneous components seen in human renal disease. At the conclusion of this project we will have the first comprehensive MRI-based evaluation of each compartment of the kidney, powerful data to inform the translation of these MRI-based biomarkers to improve human renal disease.