Tumor necrosis factor-alpha (TNFa) is a multifunctional cytokine that is expressed in the heart in response to a variety of forms of cardiac injury. Recent studies suggest that TNFa may have either beneficial or detrimental effects in the heart depending on the duration and degree of cytokine expression in the myocardium. The long term objective of this research initiative is to delineate the full spectrum of beneficial and deleterious effects that """"""""stress activated cytokines, such as TNFa, play in regulating cardiac structure and function in health and disease. The objective of this application is to delineate the mechanisms that are responsible for the deleterious effects of TNFa on cardiac structure (remodeling) and function. Two closely interrelated hypotheses will be tested: first, secretion of TNFa produces maladaptive effects on cardiac structure (remodeling) and function through activation of the type 1 TNF receptor; second, the TNF-a-induced activation of collagenolytic cascades in the heart results in degradation of the fibrillar collagen matrix. These hypotheses will be tested in four specific aims.
Specific aim 1 will determine whether overexpression of the 17 kDa secreted or the 26 kDa membrane bound for of TNF-a is responsible for producing deleterious effects on cardiac structure and function, by creating transgenic mouse colonies that express secreted (MHCsTNF) and membrane bound (MHCmTNF) TNF-a transgenes in cardiac muscle.
Specific aim 2 will determine whether the expression of the secreted form of TNF-a is responsible for producing deleterious effects by backcrossing strains of transgenic mice that overexpress the secreted form of TNF-a with TNF receptor knock-out mice lacking one or both TNF receptor types.
Specific aims and 4 will examine the role of TNF-a in the induction of a urokinase-type plasminogen activator-and matrix metalloproteinase- dependent collagenolytic cascade that results in degradation of the fibrillar collagen matrix of the heart.
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