The long-term goal of this research initiative is to delineate the cytoprotective role of proinflammatory cytokines in myocardial ischemia reperfusion (I/R) injury. We have previously shown that the cytoprotective effects of tumor necrosis factor (TNF) are conveyed by both the type 1 (TNFR1) and type 2 (TNFR2) TNF receptors. Noting that TRAF2 (tumor necrosis factor receptor associated factor 2) was the only signaling protein that was common to both receptors, we have performed experiments in isolated cardiac myocytes, as well as transgenic mice with cardiac restricted overexpression of TRAF2 (MHC-TRAF2 mice) and a dominant negative TRAF2 (MHC-TRAF2-DN mice) that have identified an indispensable role for TRAF2 in TNF mediated cytoprotective signaling. To further identify the mechanisms for the cytoprotective effects of TRAF2 we performed comparative gene expression profiling in the hearts of MHC-TRAF2 and MHC-TRAF2-DN mice and identified a unique """"""""emergency response gene"""""""" termed dysferlin, that is responsible for maintaining Ca++ dependent cardiac myocyte plasma membrane integrity. Accordingly, we propose to focus the present application on delineating the role of TRAF2 mediated membrane repair as a novel cytoprotective mechanism in I/R injury, by determining whether dysferlin is necessary and/or sufficient for mediating these effects.
Specific Aim 1 will test the hypothesis that the cytoprotective effects of TRAF2 in I/R injury ex vivo are mediated, at least in part, through dysferlin-mediated maintenance of cardiac myocyte plasma membrane integrity.
Specific Aim 2 will test whether (1) the cytoprotective effects of TRAF2 in I/R injury in vivo are mediated, at least in part, through dysferlin-mediated maintenance of cardiac myocyte plasma membrane integrity (2) and whether the beneficial effects of TRAF2 and dysferlin with respect to delimiting tissue injury in vivo are accompanied by faster time of resolution of myocardial inflammation.
Specific Aim 3 will test whether (1) the cytoprotective effects of TRAF2 are mediated, at least in part, through enhanced exocytotic membrane repair and enhanced membrane integrity in isolated rat neonatal cardiac myocytes;and (2) inducible pluripotent stem cells (iPSCs) derived human cardiac myocytes generated from dermal fibroblasts from patients with dysferlinopathy have impaired exocytosis and increased cell death following hypoxia reoxygenation injury in vitro. We expect that the results of Specific Aims 1 - 3 will provide definitive information with respect to the mechanisms for TRAF2-mediated cytoprotection in the heart, as well as allow us to determine whether dysferlin, a novel Ca++ dependent emergency response gene, is necessary and/or sufficient to mediate the cytoprotective effects of TRAF2 following I/R injury.
Studies have shown that the inflammation that occurs after a restoration of blood flow to the heart after a heart attack, has both beneficial and harmful effects. The studies proposed in the present application are designed to understand the mechanisms for the beneficial effects of inflammation in the heart by examining how inflammation allows heart muscle cells to repair their cell membranes after a heart attack, and may thus lead to the development of new therapies that help the heart to better withstand heart injury.
|Hartupee, Justin; Mann, Douglas L (2017) Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol 14:30-38|
|Tong, Carl W; Madhur, Meena S; Rzeszut, Anne K et al. (2017) Status of Early-Career Academic Cardiology: A Global Perspective. J Am Coll Cardiol 70:2290-2303|
|Mann, Douglas L (2017) High-Resolution Chromatin Mapping in Heart Failure: Some Answers, but More Questions. Circulation 136:1626-1628|
|Hartupee, Justin; Szalai, Gabor D; Wang, Wei et al. (2017) Impaired Protein Quality Control During Left Ventricular Remodeling in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor. Circ Heart Fail 10:|
|Mann, Douglas L (2017) Targeting Myocardial Energetics in the Failing Heart: Are We There Yet? Circ Heart Fail 10:|
|Marinescu, Karolina K; Uriel, Nir; Mann, Douglas L et al. (2017) Left ventricular assist device-induced reverse remodeling: it's not just about myocardial recovery. Expert Rev Med Devices 14:15-26|
|Byku, Mirnela; Mann, Douglas L (2016) NEUROMODULATION OF THE FAILING HEART: LOST IN TRANSLATION? JACC Basic Transl Sci 1:95-106|
|Hartupee, Justin; Mann, Douglas L (2016) Role of inflammatory cells in fibroblast activation. J Mol Cell Cardiol 93:143-8|
|Yang, Kai-Chun; Ma, Xiucui; Liu, Haiyan et al. (2015) Tumor necrosis factor receptor-associated factor 2 mediates mitochondrial autophagy. Circ Heart Fail 8:175-87|
|Epelman, Slava; Liu, Peter P; Mann, Douglas L (2015) Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol 15:117-29|
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