PROJECT SUMMARY While early findings suggested that hematopoietic stem cells (HSCs) depend mainly on glycolysis, emerging evidence from our lab and others has shown that mitochondrial metabolism, and particularly fatty acid oxidation, is essential to HSC fate determination. We hypothesize that mitochondrial metabolism is remodeled at the initiation of the fate choice process to meet the changing needs of proper HSC function. However, our understanding of the relationship between HSC self-renewal and lipid metabolism remains limited. A leading goal of our research is identification of the key metabolic pathways directing hematopoietic stem cell (HSC) fate decisions. The goals of our ongoing study are three-fold: (1) In Aim 1, we will induce the selective consumption of metabolites localized in the mitochondria to identify metabolic targets of fatty acid metabolism that affect HSC fate; (2) in Aim 2, we will use pharmacological or genetic modulation of key genes impacting fatty acid oxidation or its downstream targets to define the metabolic crosstalk between mitochondria and the cytosol; and (3) in Aim 3 we will evaluate the coordinated process that yields HSC division symmetry in vivo, and analysis of division balance will provide insights into the in vivo relevance of fatty acid metabolisms to HSC fate choice. If successful, our research will positively impact the field by providing a deeper understanding of the metabolic cues coordinating HSC fate decisions, and will suggest potential methods of shifting the division balance of HSCs toward self-renewal through metabolic manipulation to improve clinical outcomes after transplantation. In this diversity supplement, we propose to include Mr. Carlos Hurtado Muñoz as a primary member in our R01 project, which focuses on studying the roles of lipid metabolism in the maintenance of HSCs. Carlos is a young scientist with an impressive research background despite his age, highlighting his dedication to translational research. Throughout his undergraduate career, he devoted every summer to full-time research at various academic institutions, equipping him with the essential understanding and technical skills required to excel in our project. We will develop Mr. Hurtado Muñoz’ participation in this project as part of a structured training experience. We describe in this proposal how his project activities will involve activities that are designed to foster transferrable skills. These skills will not only be related to the field of hematology/stem cell biology but also project management, communication, leadership, and supervisory skills, and training in ethics and integrity. Mr. Hurtado Muñoz has defined his career goal explicitly as a future independent physician-scientist. Our goal during the R01 project is to give him the skills and publications that will offer the foundation to make Mr. Hurtado Muñoz an ideal candidate for the top MSTP programs in the United States. Throughout his continued involvemen...