Discovering aging-associated genetic modifiers and therapies for anthracycline-induced cardiotoxicity

Project Summary Anthracyclines are highly effective chemotherapeutics, but one of the main side effects limiting their use is cumulative dose-dependent cardiac toxicity, also known as Anthracycline-Induced Cardiotoxicity (AIC). Cardiac responses of patients to anthracyclines are highly variable, and the underlying genetic underpinnings remain largely obscure. Dr. Xu’s group has been developing zebrafish as an efficient vertebrate model for discovering genetic modifiers of AIC. Our recent screens identified fabp7 and gpnmb as two AIC modifiers, detailed studies of which suggested a novel epicardium-based aging-associated therapeutic strategy for AIC. In the meantime, Dr. Norton’s group has been carrying GWAS studies and exome sequencing of human AIC patients. A large number of clinically relevant candidate variants have been identified; however, precise genetic factors are often difficult to conclude. We reasoned that efficient zebrafish genetics could be used for experimentally testing candidate genes suggested from human GWAS studies. We have generated substantial preliminary data, prompting us to propose to demonstrate that modifier screens in zebrafish facilitate the discovery of novel susceptibility genes by testing candidate genes suggested from human GWAS studies and novel pathological events such as aging-associated epicardial remodeling. Our efforts can be divided into the following three specific aims. In Specific Aim 1, we propose to continue to study fabp7 and gpnmb, aiming to confirm their identity as therapeutic target genes for AIC. To obtain direct evidence supporting that their cardioprotective effects are related to cardiac aging, we will explore killifish, a vertebrate with a short lifespan, as a new animal model for studying cardiac aging. In Specific Aim 2, we propose to test the epicardial remodeling hypothesis by detailed expressional studies of fabp7 and gpnmb, followed by conditional genetic studies. In Specific Aim 3, we will discover additional aging-associated modifier genes via utilizing zebrafish genetics to experimentally test ~23 candidate genes suggested from GWAS studies of AIC patients. The deliverables of the proposal are: 1) we will establish epicardial remodeling as a previously unrecognized aging-associated pathological event in AIC. 2) fabp7 and gpnmb could be established as the first two epicardium-based target genes that can be harnessed for therapeutic benefits on AIC. 3) 5 additional AIC modifier genes, including about 3 with epicardial expression, could be identified. Our proposal will lead to the establishment of a fish-human platform that enables systematically discovery of AIC modifying genes.