The overall goal of this project is to develop a non-invasive, quantitative method to monitor progression of Neimann-Pick Type C (NPC) disease and its response to novel therapies. NPC disease is an inherited genetic defect that results in errant trafficking of intracellular cholesterol and gangliosides. Although it is rare, NPC is particularly devastating because most NPC sufferers present in early childhood with progressive ataxia and neurodegeneration that leads to death in the second decade of life. There is currently no effective therapy for NPC disease. However, development of new therapies is being aided by an increased understanding of the molecular mechanisms underlying NPC as well as the existence of an NPC mouse model. A major obstacle to research in NPC therapy is that current non-invasive therapeutic endpoints are limited to qualitative measures of neuromuscular response patterns or delayed onset of weight loss and death. These endpoints are far from ideal since they are neither sensitive nor quantitative. A reliable and quantitative method to monitor the progression of NPC disease and its response to successful therapy is greatly needed. Magnetic resonance imaging (MRI) has potential to be such a method. It is non-invasive and is equally applicable to investigations of animal models and human patients. In previous work within this project, we have demonstrated that the diffusion of water in white matter regions of the brain of end-stage NPC mice is significantly different than that of age-matched littermate control mice. Specifically, the fractional anisotropy (FA) of water, as measured by diffusion tensor imaging (DTI), was significantly reduced in the white matter of NPC mice. We also determined that T2-relaxation times in these regions were increased by the disease. These findings correlated with significant reductions of myelin, which is a hallmark of NPC in humans and animal models. The goal of the current project is to carefully characterize these MRI visible biomarkers, by investigating NPC mice through a continuum of the disease, and to correlate them to histological changes. The sensitivity of these markers to effective therapy will also be determined in longitudinal studies. These imaging techniques will also be used in evaluation of novel neurosteroidal therapies and in transgenic mice. Establishment of quantitative MRI methods that can be used to non-invasively follow the progression of NPC disease in animal models and in humans will expedite the development of effective therapies and add tremendous value to future clinical trials. The methodologies established in this project, while specific to NPC, will also have application to other neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000343-09
Application #
7759149
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Krosnick, Steven
Project Start
2001-04-02
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$332,357
Indirect Cost
Name
University of Arizona
Department
Type
Organized Research Units
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Deutsch, Gail; Muralidhar, Akshay; Le, Ellen et al. (2016) Extensive macrophage accumulation in young and old Niemann-Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis. Gene 578:242-50
Yoshimaru, Eriko; Totenhagen, John; Alexander, Gene E et al. (2014) Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems. Magn Reson Med 71:880-4
Erickson, Robert P (2013) Current controversies in Niemann-Pick C1 disease: steroids or gangliosides; neurons or neurons and glia. J Appl Genet 54:215-24
Totenhagen, John W; Yoshimaru, Eriko S; Erickson, Robert P et al. (2013) (1) H magnetic resonance spectroscopy of neurodegeneration in a mouse model of niemann-pick type C1 disease. J Magn Reson Imaging 37:1195-201
Borbon, Ivan A; Hillman, Zach; Duran Jr, Ernesto et al. (2012) Lack of efficacy of curcumin on neurodegeneration in the mouse model of Niemann-Pick C1. Pharmacol Biochem Behav 101:125-31
Totenhagen, John W; Lope-Piedrafita, Silvia; Borbon, Ivan A et al. (2012) In vivo assessment of neurodegeneration in Niemann-Pick type C mice by quantitative T2 mapping and diffusion tensor imaging. J Magn Reson Imaging 35:528-36
Borbon, Ivan; Campbell, Erin; Ke, Wangjing et al. (2012) The role of decreased levels of Niemann-Pick C1 intracellular cholesterol transport on obesity is reversed in the C57BL/6J, metabolic syndrome mouse strain: a metabolic or an inflammatory effect? J Appl Genet 53:323-30
Jelinek, David A; Maghsoodi, Bita; Borbon, Ivan A et al. (2012) Genetic variation in the mouse model of Niemann Pick C1 affects female, as well as male, adiposity, and hepatic bile transporters but has indeterminate effects on caveolae. Gene 491:128-34
Borbon, Ivan; Totenhagen, John; Fiorenza, Maria Teresa et al. (2012) Niemann-Pick C1 mice, a model of ""juvenile Alzheimer's disease"", with normal gene expression in neurons and fibrillary astrocytes show long term survival and delayed neurodegeneration. J Alzheimers Dis 30:875-87
Borbon, Ivan A; Erickson, Robert P (2011) Interactions of Npc1 and amyloid accumulation/deposition in the APP/PS1 mouse model of Alzheimer's. J Appl Genet 52:213-8

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