Matrix metalloproteinase-1 (MMP-1) or interstitial collagenase is a secreted protein which contributes to the etiology of many age-related degenerative diseases. Aberrant expression of MMP-1 in many cancers is also linked to both severity of disease and poor patient outcome. In recent years MMP-1 has been shown to play a prominent role in the proteolytic release and activation of growth factors, cytokines and signaling peptides which also have the potential to modulate the senescent microenvironment. The regulatory mechanisms that control senescence associated (SA) MMP-1 expression are unknown. Our findings indicate that oxidants play an important role in regulating MMP-1 expression. This application seeks to define whether oxidant-sensitive signaling networks are responsible for age associated increases in MMP-1 production. We will test the hypotheses that redox activation of Jun-N-Terminal Kinase (JNK) is responsible for the age-dependent increases in MMP-1 expression and that this redox-sensitive signaling pathway controls the activity of the Ets-1 transcription factor and chromatin remodeling events that lead to enhanced MMP-1 expression. Our studies are divided into four specific aims:
Aim 1 will determine,1) if the SA increase in MMP-1 expression is sensitive to molecular or pharmacologic inhibition of JNK activity, 2) whether JNK activation is redox-responsive and 3) if SA MMP-1 expression is attributed to oxidative-inactivation of JNK regulatory phosphatases;
Aim 2 will determine, 1) the redox responsive regulatory regions of the MMP-1 promoter that contribute to its senescence expression, 2) whether Ets-1 recruitment to the MMP-1 promoter is SA and redox- responsive, and 3) evaluate if senescence leads to the selective utilization of the SNP containing MMP-1 allele that is commonly associated with enhanced frequency and susceptibility to certain cancers;
Aim 3 will determine the oxidant-sensitive chromatin modifying and remodeling events that control senescence associated MMP-1 production;
and Aim 4 will determine, using a murine aging model of oxidative stress, if antioxidant based therapies are effective in, 1) decreasing the steady state production of H2O2, 2) modulating kinase signaling and 3) decreasing the SA expression of MMPs. We have aligned ourselves with experts in the fields of aging biology, free radical chemistry and genetics to develop a proposal which tackles relevant issues related to both aging and tumor biology and that were outlined in the PA-07-278, The Secretory Pattern of Senescent Cells. The underlying overall hypothesis is that the permissive nature of the senescent microenvironment to degenerative disease is attributed to SA oxidant production and aberrant MMP production. Finally, and perhaps most importantly, it is anticipated that our studies will fundamentally advance our understanding of the contribution of free radicals to many SA diseases. Public Health Relevance. The process of aging is associated with many degenerative disease processes including arthritis, atherosclerosis, cancer and neurodegeneration. Associated with many of these disease processes is the uncontrolled expression of matrix metalloproteinase-1. Our laboratory has established that the age-associated increases in MMP-1 expression can be prevented by antioxidant-based therapies. A fundamental understanding of how the various antioxidant compounds block matrix metalloproteinase-1 production is essential for the design of safe and effective therapeutic strategies for the future treatment of many age associated degenerative diseases.
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