Lipid metabolism and renal injuries: Our research investigates novel mechanisms that could lead to identifying new drug targets for preventing or treating radiation nephrotoxicity (RN) in cancer survivors. RN lacks an effective known molecular target, so we explored the role of sphingolipids in radiation-induced podocyte injury. Our findings revealed early cytoskeletal remodeling, down-regulation of SMPDL3b, and increased cellular ceramide levels as key factors in radiation injury. To assess renal damage noninvasively in conscious mice, we developed a rapid and cost-effective method for measuring glomerular filtration rate (GFR). Additionally, we studied the role of cholesterol metabolism in renal injury. LXR agonists have shown promise in reducing proteinuria, renal inflammation, and glomerular cholesterol content in diabetic mice by upregulating ABCA1. However, these agonists also increase plasma and liver triglycerides, limiting their clinical use. We identified 5-aryl nicotinamide compounds that target OSBPL7 and upregulate ABCA1-dependent cholesterol efflux through phenotypic drug discovery. This approach offers an alternative mechanism to enhance ABCA1 and presents a promising new therapeutic strategy for treating renal diseases and other disorders related to cellular cholesterol homeostasis. In future studies, we aim to explore further the regulatory mechanisms of intracellular cholesterol accumulation and its signaling processes. By understanding how normal cells become sensitive or tumor-resistant to radiation therapy and Chemotherapy, we hope to uncover valuable insights to improve cancer treatment efficacy.

Total body irradiation (TBI), Chemotherapy, and HSCT in renal injuries: Our research focuses on understanding the mechanisms of renal damage caused by total body irradiation (TBI), Chemotherapy, and hematopoietic stem cell transplantation (HSCT). In a murine model, we explore how TBI or HSCT affects lipid metabolism in normal kidney and cancer cells, leading to renal injury and treatment resistance. Our findings suggest lipid accumulation contributes to glomerular basement membrane (GBM) thickness and reduced renal function. We have also identified how radiation therapy (RT) induces podocyte injury and increases GBM thickness, resulting in albuminuria. Future studies will investigate the effects of different treatment doses on GBM components and cholesterol metabolism in renal injury. Additionally, we are studying the impact of platinum-based chemotherapeutic drugs and RT on cholesterol homeostasis in renal and tumor cells. We aim to understand the contributions of cholesterol uptake, synthesis, and efflux in treatment-induced renal injuries and tumor resistance. To address nephrotoxicity associated with cisplatin therapy, we are exploring lipid-depleting agents to enhance platinum drugs' efficacy while preventing renal toxicity.

Collectively, the projects in my lab have been comprehensive, covering various aspects of cancer research. We have delved into the mechanisms of normal tissue toxicity, focusing on nephrotoxicity. Additionally, our research involves studying cancer development, exploring potential therapeutic avenues, and investigating cancer predisposition. This diverse and robust research effort contributes significantly to the field of cancer research.