This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A long term goal of this proposal is to delineate the mechanisms by which protein surplus cardiomyopathies (PSCs) progress to congestive heart failure. PSCs are an emerging group of cardiomyopathies. Crystallinopathy caused by the mutation of the alphaB-crystallin (CryAB) gene, often presents as desmin-related cardiomyopathy (DRC) and exemplifies PSCs. DRC is characterized by aberrant desmin aggregation in muscle cells and this aggregation appears to play a central role in DRC pathogenesis. Notably, similar protein aggregates were also observed in human congestive heart failure (CHF) resulting from idiopathic dilated cardiomyopathy, a common heart disease. However, it remains unclear how abnormal protein aggregation affects myocyte functions. The current proposal focuses on the ubiquitin-proteasome system (UPS) mediated protein turnover, a cellular process essential to virtually all aspects of cell function. The central hypothesis is that aberrant protein aggregation characteristic of DRC impairs proteolytic function of the UPS, representing a nodal pathogenic process in PSCs.
These specific aims will be pursued: (1) To test whether CryAB has an obligatory role in UPS function and to define a correlation (likely a causal relation) between aberrant protein aggregation arid UPS impairment in intact mice. The underlying hypothesis is that aberrant protein aggregation instead of loss-of-function of CryAB impairs the UPS in crystallinopathic hearts. (2) To test a cause-effect link between aberrant protein aggregation and UPS impairment in cell culture. This is to test the hypothesis that formation of protein aggregates through expression of a mutant CryAB is sufficient to compromise UPS function. (3) To discover the identities of ubiquitylated proteins accumulated in crystallinopathy mouse hearts using proteomics. Underlying hypothesis is that accumulated ubiquitylated proteins include structural proteins and physiologically important regulatory proteins.
|O'Connell, Timothy D; Block, Robert C; Huang, Shue P et al. (2017) ?3-Polyunsaturated fatty acids for heart failure: Effects of dose on efficacy and novel signaling through free fatty acid receptor 4. J Mol Cell Cardiol 103:74-92|
|Eclov, Julie A; Qian, Qingwen; Redetzke, Rebecca et al. (2015) EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4. J Lipid Res 56:2297-308|
|Savinova, Olga V; Fillaus, Kristi; Harris, William S et al. (2015) Effects of niacin and omega-3 fatty acids on the apolipoproteins in overweight patients with elevated triglycerides and reduced HDL cholesterol. Atherosclerosis 240:520-5|
|McKenzie, Casey W; Craige, Branch; Kroeger, Tiffany V et al. (2015) CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice. Mol Biol Cell 26:3140-9|
|Kobayashi, Satoru; Liang, Qiangrong (2015) Autophagy and mitophagy in diabetic cardiomyopathy. Biochim Biophys Acta 1852:252-61|
|O'Connell, Timothy D; Jensen, Brian C; Baker, Anthony J et al. (2014) Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66:308-33|
|Savinova, Olga V; Fillaus, Kristi; Jing, Linhong et al. (2014) Reduced apolipoprotein glycosylation in patients with the metabolic syndrome. PLoS One 9:e104833|
|Jensen, Brian C; O?Connell, Timothy D; Simpson, Paul C (2014) Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation. J Cardiovasc Pharmacol 63:291-301|
|Wu, Steven C; Dahl, Erika F; Wright, Casey D et al. (2014) Nuclear localization of a1A-adrenergic receptors is required for signaling in cardiac myocytes: an “inside-out” a1-AR signaling pathway. J Am Heart Assoc 3:e000145|
|Xu, Xianmin; Kobayashi, Satoru; Chen, Kai et al. (2013) Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J Biol Chem 288:18077-92|
Showing the most recent 10 out of 65 publications