Ji Zhang, Ph.D
Assistant Professor of Pediatrics
Primary Appointment:Department of Pediatrics
- Postdoctoral Fellowship:Memorial Sloan Kettering Cancer Center
- PhD:. University of Tennessee Health Science Center
Current Research Interests:
My lab is interested in understanding the role of metabolic pathways in normal and malignant hematopoiesis. Alteration of cellular metabolism has emerged as a determinant of cell fate. In the setting of cancer, transformation-associated changes in the regulation of cell growth and proliferation can result in specific nutrient or metabolic enzyme dependencies that are absent in non-transformed cells. In addition, nutrient limitation in the tumor environment can place further stress on tumor cells. As they grow, tumor cells become increasingly dependent on adaptive stress responses to circumvent nutrient restriction. The adaptive stress responses that a tumor comes to depend on are dictated by the intrinsic properties of the tumor cells and the environment in which it resides. Similar to tumor cells, hematopoietic cells reside in a niche where nutrient supply is tightly regulated. Therefore, defining the metabolites and the adaptive stress response pathways on which normal and malignant hematopoietic cells depend will facilitate the development of better therapeutic strategies to treat hematopoietic diseases.
1. L-asparaginase based therapy in acute lymphoblastic leukemia (ALL). L-asparaginase has been used for decades to treat pediatric ALL. It functions by depleting asparagine, a nonessential amino acid, from the circulation, suggesting a unique dependency on asparagine for ALL cells to grow and survive. However, patients can develop resistance to L-asparaginase treatment. We will study the adaptive stress response pathways in conferring resistance to L-asparaginase treatment, in the hope of identifying novel therapeutic targets to enhance the efficacy of L-asparaginase treatment.
2. Role of nonessential amino acid metabolism in lymphocyte function. Accumulating evidence suggests that tumor cells compete with normal lymphocytes for nutrients as a way to escape immune-surveillance. To understand how lymphocytes adapt to nutrient limitation will facilitate the development of better strategies for immunotherapy. We will determine the role of glutamine/asparagine metabolism during naïve T cell activation and differentiation, and whether we can manipulate amino acid availability or the adaptive stress response pathway to modulate lymphocyte function.
3. Metabolic regulation of hematopoietic stem cells (HSCs). Similar to malignant cells, normal HSCs rewire their metabolism to sustain stem cell properties. In this regard, a key metabolic feature of HSCs is their reduced dependence on oxidative phosphorylation, which helps to prevent the accumulation of oxidative stress. Using genetic approaches, we will determine how HSCs mitigate oxidative stress through metabolic switch, which can influence their potential to transform into leukemia.
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