Grant: CIHR Fellowship

The hematopoietic system populates the cellular components of the blood throughout the lifespan from a limited number of hematopoietic stem and progenitor cells (HSPCs) and failure of this system manifests in a variety of blood disorders including cancer. A major consequence of aging is the random accumulation of genetic mutations in somatic cells; it is established that specific mutations occur at high frequencies in the blood of individuals >50 years old indicating that the hematopoietic system is relying on fewer HSPCs, or clones, resulting in a condition termed clonal hematopoiesis (CH). This is problematic as the most common mutations in CH are also implicated in the development of blood cancers and cardiovascular disease. Because the accumulation of genetic mutations is progressive, starting early in life, traditional interventions that have accompanying side effects when taken for long periods, such as pharmaceuticals, are not feasible. The most successful interventions for restoring HSPC function in old animals have been metabolic in nature. The proposed research will build upon tools built in our laboratory that model CH by replicating CH driving mutations in the zebrafish. Furthermore, these tools allow for the quantification of CH and isolation of clonally dominant and non-dominant HSPCs using fluorescent proteins and DNA barcoding. Using these tools, we will explore how the metabolic state of clonally dominant and nondominant HSPCs differ and use this information to identify vulnerabilities that can be targeted with metabolic interventions to slow CH development. Furthermore, we will explore which dietary supplements, with known safety profiles, may be leveraged to abate the progression of CH. The results of this research will give us an unprecedented insight into how CH affects metabolism and how we can develop sustainable, long-term interventions to prevent aging-associated blood disorders.