Public Abstract

DE-SC0025417: Modeling the Circadian Effects of Low Dose Radiation on Immunometabolism and Its Effect on Liver Organoid Physiology

Award Status: Active

Institution: Rensselaer Polytechnic Institute, Troy, NY
UEI: U5WBFKEBLMX3
DUNS: 002430742

Most Recent Award Date: 09/17/2024
Number of Support Periods: 1
PM: Kulkarni, Resham

Current Budget Period: 09/01/2024 - 08/31/2025
Current Project Period: 09/01/2024 - 08/31/2027
PI: Hurley, Jennifer

Supplement Budget Period: N/A

Public Abstract

Title: Modeling the Circadian Effects of Low Dose Radiation on Immunometabolism and Its Effect on Liver Organoid Physiology J. Hurley, Rensselaer Polytechnic Institute (Principal Investigator) E. Blaber, (Co-Principal Investigator), S. Baker, (Co-Investigator) Low dose radiation (LDR) affects multiple physiological systems, including the human immune response and metabolism. Several hallmarks of the immune system have been shown to be affected after exposure to LDR, leading to an alteration in immunity, and an increase in oxidative stress and inflammation. This affects both the innate immune system, such as monocyte derived macrophages, and the adaptive immune system, including T cell populations. Furthermore, we and others have shown that Non-Alcoholic Fatty Liver Disease (NAFLD), a chronic condition that affects more than 25% of adults globally, develops in response to chronic exposure to environmental hazards like oxidative stress and radiation exposure. Although the liver has some regenerative capacity to combat damage from environmental hazards, this ability is dependent on a delicate balance and specifically timed immune response including both pro-inflammatory and reparative immune populations, suggesting that the effect of LDR on the immune system is acutely detrimental to the liver’s regenerative capability. A key regulator of the immune response is the circadian clock, the 24-hour mechanism that coordinates biology to the persistent day night cycle. The clock times metabolism and oxidative stress to regulate immune pathways so that the immune response is primed to deal with environmental stresses differently depending on the time of day of exposure to those stresses. In fact, the clock was shown to temporally regulate the release of some immune molecules in response to LDR. However, despite the known interconnection between the immune system, LDR, and the clock, little is known mechanistically about how time-of-day of exposure to LDR affects the immune response of an organism and the consequent effects on highly metabolic organs such as the liver. Therefore, in this proposal, we aim to address this specific knowledge gap by investigating how the timing of both acute and chronic exposure to LDR will affect time-of-day specific differences in both immune populations and the liver. We expect that time-of-day exposure to LDR will generate different responses in immune cell function that affect the regulation and repair of liver cells. We will accomplish this project by investigating the cellular behavior and metabolic phenotypes of peripheral macrophages, regulatory T-cells, and hepatic organoids to determine time-of-day specific changes induced by LDR. We will specifically use AI/ML predictive algorithms with multi-omics methods to forecast key target molecules inducing cellular dysfunction in each population of cells. We will also identify the time-of-day effects of LDR exposure of immune cells on the physiology of liver organoids using custom microfluidics Microphysiological systems (MPS). Together, this research will significantly advance our understanding of how circadian rhythms affect the physiological response to both acute and chronic LDR exposure. Furthermore, it will provide multi-omic mechanistic insight into the pathways and cellular responses that cause both immune dysregulation and progression of fibrotic liver disease in response to LDR exposure.

Title: Modeling the Circadian Effects of Low Dose Radiation on Immunometabolism and Its Effect on Liver Organoid Physiology

J. Hurley, Rensselaer Polytechnic Institute (Principal Investigator)

E. Blaber, (Co-Principal Investigator), S. Baker, (Co-Investigator)

Low dose radiation (LDR) affects multiple physiological systems, including the human immune response and metabolism. Several hallmarks of the immune system have been shown to be affected after exposure to LDR, leading to an alteration in immunity, and an increase in oxidative stress and inflammation. This affects both the innate immune system, such as monocyte derived macrophages, and the adaptive immune system, including T cell populations. Furthermore, we and others have shown that Non-Alcoholic Fatty Liver Disease (NAFLD), a chronic condition that affects more than 25% of adults globally, develops in response to chronic exposure to environmental hazards like oxidative stress and radiation exposure. Although the liver has some regenerative capacity to combat damage from environmental hazards, this ability is dependent on a delicate balance and specifically timed immune response including both pro-inflammatory and reparative immune populations, suggesting that the effect of LDR on the immune system is acutely detrimental to the liver’s regenerative capability.

A key regulator of the immune response is the circadian clock, the 24-hour mechanism that coordinates biology to the persistent day night cycle. The clock times metabolism and oxidative stress to regulate immune pathways so that the immune response is primed to deal with environmental stresses differently depending on the time of day of exposure to those stresses. In fact, the clock was shown to temporally regulate the release of some immune molecules in response to LDR. However, despite the known interconnection between the immune system, LDR, and the clock, little is known mechanistically about how time-of-day of exposure to LDR affects the immune response of an organism and the consequent effects on highly metabolic organs such as the liver. Therefore, in this proposal, we aim to address this specific knowledge gap by investigating how the timing of both acute and chronic exposure to LDR will affect time-of-day specific differences in both immune populations and the liver. We expect that time-of-day exposure to LDR will generate different responses in immune cell function that affect the regulation and repair of liver cells. We will accomplish this project by investigating the cellular behavior and metabolic phenotypes of peripheral macrophages, regulatory T-cells, and hepatic organoids to determine time-of-day specific changes induced by LDR. We will specifically use AI/ML predictive algorithms with multi-omics methods to forecast key target molecules inducing cellular dysfunction in each population of cells. We will also identify the time-of-day effects of LDR exposure of immune cells on the physiology of liver organoids using custom microfluidics Microphysiological systems (MPS). Together, this research will significantly advance our understanding of how circadian rhythms affect the physiological response to both acute and chronic LDR exposure. Furthermore, it will provide multi-omic mechanistic insight into the pathways and cellular responses that cause both immune dysregulation and progression of fibrotic liver disease in response to LDR exposure.