Melov Lab

Overview

The Melov laboratory focuses on the production of damaging free radicals within the powerhouses of the cell, the mitochondria, as a significant component of aging and age-related diseases.

Mitochondrial Oxidative Stress and Aging

To better understand the effects of endogenous oxidative stress in mammals, we are investigating the consequences of genetic inactivation of mitochondrial superoxide dismutase (SOD2) in the mouse, the chief mitochondrial defense against ROS in the cell. We are studying the various phenotypes that arise in this mouse via histopathological analysis at the light and ultramicroscopic levels, as well as biochemical analyses, genomic and proteomic analyses, and survival analysis. The SOD2 nullizygous mouse lives approximately seven days, and dies from a complex phenotype, including dilated cardiomyopathy, hepatic lipid accumulation, ketosis, anemia, neurodegeneration, and a severe spongiform encephalopathy associated with profound neurological disturbances. But the life span of these mice can be extended by approximately three- to fourfold, via treating the mouse with synthetic catalytic antioxidants, and many of these phenotypes are attenuated or rescued through chronic antioxidant treatment. The antioxidants we use are small molecular weight catalytic SOD and catalase mimetics, and are efficacious in a number of animal models of oxidative stress. Recent findings include the identification of particular mitochondrial proteins that are sensitive to mitochondrial oxidative stress, as well as the demonstration of rescue of function through antioxidant treatment. Gene expression profiling has been a significant component of our work in the last year as well. Further, we have been investigating the potential mutagenic effects of mitochondrial oxidative stress through studies examining genomic stability in cell lines, and tissues derived from the SOD2 mouse.

Pharmacogenomic and proteomic profiling of mitochondrial oxidative stress and aging, and age-related disease

A powerful approach for furthering our understanding of the molecular targets of endogenous mitochondrial oxidative stress is pharmacogenomic and proteomic profiling. Our approach utilizes the SOD2 nullizygous mouse in combination with antioxidant treatment, and the methodologies of gene expression and proteomic profiling. Gene expression profiling is the simultaneous quantitation of thousands of genes of interest from a given cell type or tissue versus a control. We have been characterizing patterns of gene expression in animal models of aging, including the SOD2 nullizygous mouse with and without antioxidant treatment, normal aging wildtype mice (with and without antioxidant treatment), and aging Caenorhabditis elegans. The pharmacogenomic approach facilitates our ability to determine the physiological state of an individual tissue, through identification of a characteristic profile.

Oxidative stress and Alzheimer’s disease

We have also been investigating the potential of antioxidant compounds to attenuate or reduce the pathology associated with the expression of Aß in a mouse model of Alzheimer’s disease. The Tg2576 mouse model of Alzheimer’s disease is arguably the best characterized mouse model of Alzheimer’s disease, and it has been extensively studied since its development in 1996. Therapeutic approaches that have proven efficacious in reducing Aß load in these mice have also proven effective in phase II trials in humans, thereby demonstrating the utility of this model for the evaluation of candidate molecules against Alzheimer’s disease. Alzheimer’s disease is associated with oxidative stress in the brains of patients as well as in the Tg2576 mouse. We have created a number of genetic variants of this mouse model of Alzheimer’s disease in order to better understand the development of Alzheimer-like pathology.

Genomics and aging

A central question in aging research is how variation in life span is modulated within a species. Therefore we are comparing different strains of C. elegans for various molecular traits to gain insight into processes that modulate aging. Addressing this question uses a number of genetic, molecular, and morphological approaches in strains of nematodes. All C. elegans nematodes are genetically identical at birth, yet substantial variation develops over the course of their lives, such that at the end, they can be dramatically different at multiple levels. Our studies seek to understand the source of this variation and how it affects individual life span. Recent studies have looked at expression profiles of aging human beings compared to young individuals. We have found that exercise can reverse a characteristic aging profile back to youthful levels.