The overall aim of this grant, Cardiovascular Control in Normal and Disease States , is to identify physiological, biochemical and molecular mechanisms, e.g., apoptosis, which are fundamental to the progression from imposition of the abnormal load to development of heart failure (HF). This grant has been the principal support for the PI's laboratory since 1972. During the current funding period a novel primate model of permanent coronary artery occlusion (CAO) for 2-3 months with or without superimposition of pacing-induced HF was developed. Data gathered from this model provides the cornerstones for the current renewal proposal, which are summarized in 4 hypotheses: (A) Apoptosis, a cardinal feature of HF, actually occurs primarily in non-myocytes, and moreover, appears to be salutary, rather than deleterious, in the remodeling process following chronic CAO;(B) Autophagy, a mechanism that can be either salutary or deleterious, exerts an adverse effect on the remodeling process and left ventricular (LV) function. Accordingly, inhibition of this mechanism is beneficial following chronic CAO;(C) Proteasome inhibitors following chronic CAO attenuate the LV hypertrophy in the remote and adjacent myocardium and improve LV function;and (D) Non-biased genomic and proteomic experiments in the monkey model of chronic CAO with and without HF will uncover novel mechanisms mediating the remodeling and HF, e.g., the cardiac expression of a gene encoding a novel cell cycle-related kinase (CCRK) is dramatically downregulated in the primate model of chronic myocardial ischemia (MI) and HF. The major aims of the current proposal are based on these observations and will be addressed using traditional histopathological and physiological techniques combined with genomics and proteomics in monkeys and genetically altered mouse models. Despite recent advances in the treatment of CAO and HF, the overall impact on morbidity and mortality has been limited, and HF following chronic coronary artery disease remains the pre-eminent cardiovascular health problem in the country. Accordingly, it will be important to develop new therapeutic approaches. There are potential therapeutic modalities that could emanate from this proposal, e.g., inhibition of proteasome activity or autophagy and development of new therapies based on novel molecules discovered in the novel monkey model of MI and HF.
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