The role of Syndecan-2 in hematopoietic stem cell maintenance and regeneration

ABSTRACT Hematopoietic stem cells (HSCs) maintain the adult blood and immune systems throughout the lifetime of an organism. While HSC transplants are used clinically for the curative treatment of patients with leukemias, lymphomas, and immune disorders, the success of HSC transplants varies considerably, with some patients having to undergo multiple transplants due to inefficient HSC engraftment. The goal of the proposed project is to identify how the heparan sulfate proteoglycan, Syndecan-2, regulates HSC maintenance and regeneration. Aim 1 will utilize newly generated tissue-specific knockout mice to analyze the contribution of Syndecan-2 in regulating HSC engraftment, while performing a structure-function analysis of the molecular motifs of Syndecan- 2 in mediating engraftment and niche regeneration. Aim 2 will analyze the role of Syndecan-2 in regulating hematopoietic recovery from stress by combining radiation injury and myelosuppression in vivo models of HSC self-renewal. These experiments will demonstrate the role of Syndecan-2 in mediating HSCs maintenance and regeneration, providing foundational knowledge to enable further study of how proteoglycans regulate HSCs. The knowledge procured from the completion of the proposed aims is expect to have broad potential contributions to patients undergoing chemotherapy and radiation therapy as a part of their treatment regimen for variety of cancers, immune diseases, leukemias and anemias and therapeutic value from a public health standpoint for treating patients that experience accidental radiation exposure. My career goals are to become an assistant professor at a top-tier academic research institution. I aim to lead a research program that investigates how proteoglycans regulate HSCs and the HSC microenvironment at homeostasis and during stress. To achieve these goals, the proposed project has embedded training in modeling HSC recovery from injury, while expanding my knowledge of glycobiology and growth factor signaling. Under this award, I will pursue the proposed training with the mentorship of Dr. John Chute (UCLA), who has substantial experience in translational modeling of HSC and niche regeneration, while supported by an Advisory Committee with expertise in stem cell biology, growth factor signaling and proteoglycan biology. As a postdoctoral fellow, I will present my work at international conferences and to my mentoring committee, which consists of experts in the field. As junior faculty, I will receive training in laboratory management/leadership, grant writing, negotiation, and mentoring to help me lead a successful research team. The proposed project will allow me to transition to an independent research position while developing my skillset in HSC biology. UCLA has superb research facilities, professional development resources and administrative support, which will provide the necessary infrastructure to support my research and career development as a mentored postdoctoral fellow and ultimately, my transition to independence.