Grants and Contracts Details
Aging is a major risk factor for coronary heart disease. People age 65 and older are more likely than younger people to develop ischemic heart diseases, often caused by heart attack (myocardial infarction, MI). This injury causes myocardial necrosis, rendering many patients progress to heart failure (HF) within five years of initial MI. Unfortunately, the human heart does not regenerate after injury, and there is no approved clinical treatment that facilitates cardiac repair. Moreover, no regenerative mammalian models are established to identify molecular targets for cardiac repair after an acute injury or age-associated damage. This proposal will address these limitations by studying regenerate mammal with non-regenerator simultaneously. Acomys (African Spiny mice) is a mammal closely related to Mus (laboratory mouse). Recently, independent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs. Most importantly, after MI, Acomys demonstrated significant cardiac protection, with a higher survival rate than mice. Our preliminary studies revealed that Acomys hearts retained a high frequency of young, proliferative phenotype cardiomyocytes, and is capable of rescuing cardiac function after MI. This proposal will further dissect the mechanisms driving the youthful cardiac phenotype and cardiac protection in Acomys. I will study Acomys and Mus side by side to test my central hypothesis that unique intrinsic response to reactive oxygen species (ROS) preserves proliferative CM into adulthood and drives enhanced cardiac repair in Acomys after a heart attack. In the F99 phase of this proposal, I will continue investigating the contribution of Acomys cardiomyocytes in endogenous cardiac repair following MI in both young and aged animals. Specifically, I will examine cardiomyocyte proliferation in both species after MI. Scar size, cardiac function, and angiogenesis will also be characterized to determine the extent of recovery. In the K00 phase, I will switch focus to identify molecular targets and pathways that allow Acomys to maintain a “young heart” into adulthood. The proposed work will yield valuable information on endogenous cardiac repair in adult mammals. This knowledge will aid in the discovery of novel therapies and approaches for maintaining cardiac health across the lifespan.
|Effective start/end date||9/1/20 → 8/31/21|
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