This grant will support a five year period of rigorous training for the development of a career as an independent investigator in academic cardiology. The principal investigator has completed a clinical fellowship in cardiology and echocardiography at Massachusetts General Hospital and seeks to expand his scientific skills, and his interest in the mechanisms of cardiomyocyte response to stress, using a unique integration of resources. This proposal seeks to investigate the role of IKKB and NF-kB signaling in the heart at baseline and under the stress of pressure overload. The candidate will be under the mentorship of Dr. Anthony Rosenzweig, the Director of Cardiovascular Research at Beth Israel Deaconess Medical Center, who has expertise in the field of cardiac hypertrophy, heart failure and remodeling, and kinase signaling pathways. A curriculum encompassing both research and didactic training has been devised to further the training of the candidate, and an advisory committee of leading medical researchers will provide scientific and career advice. In addition to weekly laboratory meetings and more frequent informal discussions, Dr. Rosenzweig's laboratory, as part of the Cardiovascular Research Center at BIDMC, expects participation in weekly journal club, work-in-progress presentations, and research seminar delivered by visiting faculty, as well as bimonthly joint lab meetings with other groups in the Longwood Medical Area with a focus on cardiac hypertrophy and remodeling and cardiovascular genetics. The laboratory is located in the Longwood Medical Area in Boston, a rich environment offering a wide range of research seminars and lectures, and within steps of Harvard Medical School campus where the candidate's didactic program will be pursued. The Nuclear Factor of kappa B cells (NF-kB) family of transcription factors regulates a wide range of essential processes in multiple tissues, from inflammation to cell survival. In the heart, while it is known that NF-kB is involved in hypertrophy, ventricular remodeling, and ischemic injury, its precise role remains incompletely defined. Prior studies have sought to establish a protective or detrimental role for NF-kB;these studies have used transgenic approaches or pharmacological inhibitors of NF-kB and have yielded contradictory results. As a result, an important unanswered question is whether NF-kB represents a therapeutic target for inhibition. NF-kB inhibition is also being considered in cancer and diabetes, which could affect cardiovascular health. Understanding NF-kB's role in the heart thus has important practical implications. The serine-threonine kinase, Inhibitor of Kappa B Kinase beta (IKKB), is the primary activator of NF-kB in response to inflammatory and hemodynamic stimuli (reviewed in ). To investigate the role of NF-kB in the heart, our laboratory has generated mice with cardiac specific gene inactivation of Ikbkb (IKKB gene). Two different gene deletion strategies were employed both Cre and an activatable Crefusion protein to generate both constitutive and inducible cardiac restricted knockout strains. Unexpectedly, preliminary data suggest that constitutive IKKB deletion produces moderate contractile dysfunction in young mice associated with altered cardiomyocyte (CM) calcium handling. The goals of this proposal are to define the role of IKKB in this baseline cardiac phenotype and in a model of pressure overload induced hypertrophy. This proposal is based on the following hypotheses: 1) NF-kB activation in the heart requires IKKB, 2) IKKB promotes normal CM function through modulation of calcium cycling, and 3) IKKB inhibits CM apoptosis in most settings through regulation of NF-kB dependent transcription. To test these hypotheses, we will utilize mice with cardiac specific inactivation of IKKB at baseline and under the stress of pressure overload.
In Specific Aim 1, we will characterize the cardiac specific IKKB deleted mice at baseline.
In Specific Aim 2, we will investigate the signaling mechanisms and the patterns of altered gene expression in the IKKB deleted mice which relate to the observed phenotype.
In Specific Aim 3, we will test the hypothesis that loss of IKKB signaling will lead to abnormally severe cardiac dysfunction under pressure overload as a result of increased CM apoptosis. Completion of these aims will contribute a deeper understanding of the ways in which the protective and deleterious effects of NF-KB activation are balanced in different conditions, as well as the distinct functions that this activation may have at different stages of development.
NF-kB is an essential mediator of inflammatory and survival signaling in the heart;the serine/threonine kinase IKKB is activated in heart disease and is required for NF-kB activation. Whether IKKB/NF-kB activation in heart disease is adaptive, protective, or deleterious is a point of controversy;some investigators have suggested that NF-kB inhibition should be considered as a therapeutic approach in heart disease and others have raised concerns that this would lead to deleterious effects. IKKB inhibition is also under consideration as therapy for other diseases including cancer and diabetes all of these issues warrant a better understanding of the role of IKKB in the heart.
|Coggins, Matthew; Rosenzweig, Anthony (2012) The fire within: cardiac inflammatory signaling in health and disease. Circ Res 110:116-25|