Public Abstract

DE-SC0025474: Exploring T Cell functional dynamics following low-dose radiation exposure: insights into metabolic and other regulatory alterations using a multi-omics systems biology approach

Award Status: Active

Institution: Georgetown University, Washington, DC
UEI: TF2CMKY1HMX9
DUNS: 049515844

Most Recent Award Date: 09/27/2024
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: Fornace, Albert

Supplement Budget Period: N/A

Public Abstract

Low-dose radiation (LDR), emanating from natural sources, medical procedures, or workplace environments, can affect the general population. Importantly, LDR can significantly impact the immune system by changing its balance, metabolism, and overall function. Immune cells have critical roles in combating infections as well as cancer prevention, and disturbances can result in autoimmune diseases. While many studies focus on higher doses of radiation, even low doses can alter immune health, as seen in various global reports. Understanding how LDR affects immune responses, especially in radiosensitive immune cells like T lymphocytes, is crucial for accurate health risk assessments. T cells are vital for the adaptive immune response and are highly sensitive to radiation. Though changes in T cells are well-documented at medium or high radiation doses, there's a gap in our knowledge about how LDR affects these cells and immune responses. Therefore, our aim is to address the gaps in understanding LDR-induced immune alterations, focusing on T cell metabolic dysregulation, through a combination of well-controlled humanized and wild-type mouse models, immunologic studies, and integrative analyses “multi-omic’ datatsets that measure amounts and properties of genes, proteins and metabolites. In this project, we focus on radiation doses of 10 cGy or less and use a multi-omics approach, which includes studying metabolites, gene expression, proteins, and epigenetic changes. Our previous research and preliminary data show that LDR can cause lasting molecular changes. Notably, we have shown that LDR does have measurable impacts on T cell metabolism and gene expression related to energy metabolism. We plan to use the animal models to examine the impact on T cell function in response to antigen challenge, and the effects on the thymus, which plays a pivotal role in orchestrating T cells’ maturation. Our in-depth multi-omics approach will analyze changes in signaling pathways after LDR exposure. Metabolomics, which studies small molecules, i.e. metabolites, within cells, will be central to our research as it provides dynamic insights into how T cell function can be disturbed in response to LDR. This approach will complement other omics data and help us understand how genetic and transcriptomic changes lead to altered metabolic phenotypes and T cell immune responses. We will create a network map showing interactions between genes, proteins, and metabolites, which will serve as a resource for further hypothesis generation and integration with ongoing studies at DOE laboratories. Our research has three main aims, each designed to provide a comprehensive understanding of how LDR impacts T cell function and overall immune health: Aim 1: Deciphering thymus microenvironment responses to LDR in T cell maturation. This includes studying alterations in cellular composition, multi-omic profile, and molecular interactions within the thymus,an organ crucial for the development and maturation of T cells. Aim 2: Examine LDR effects on mature T cell responses and assessing age-related impacts. This aim focuses on the effects of LDR on mature T cells, which are fully developed and actively participate in immune responses. We will assess how LDR influences T cell functionality, including their ability to respond to SARS-CoV-2 mRNA vaccination, which serves as antigens that trigger an immune response. Additionally, we will explore how these effects vary with age, given that aging can alter immune responses and increase susceptibility to radiation. Aim 3: Multi-omic data management, integration, and interpretation. We will integrate findings from metabolomics, transcriptomics, proteomics, and epigenomics.Using advanced AI and machine learning techniques, we will create detailed maps of the molecular regulatory networks affected by LDR. These maps will illustrate the interactions between genes, proteins, and metabolites, providing a comprehensive view of how LDR impacts immune function. The integration of these multi-omic datasets will enable us to identify key molecular drivers of LDR-induced changes, offering new insights into the mechanisms underlying these effects. Studying LDR is challenging because the molecular responses can be complex but subtle. Therefore, choosing the right model systems is crucial. Our planned studies on T cells are significant, as we've already observed clear responses within DOE’s preferred low dose range. Both short-term and long-term immune effects of LDR are relevant to human health, as shown in population studies. Our research will provide a detailed understanding of how LDR influences T cell development, functionality, and the broader immune system. This knowledge is crucial for developing accurate health risk assessments and for creating strategies to mitigate the adverse effects of LDR exposure on human health. To maximize the utility of our data, we will make our multi-omic datasets publicly available, allowing for integration with other research programs like the Low-dose Understanding, Cellular Insights, and Molecular Discoveries (LUCID) program. All data and code will be publicly accessible to ensure reproducibility and to benefit the broader radiation research community.

Low-dose radiation (LDR), emanating from natural sources, medical procedures, or workplace environments, can affect the general population. Importantly, LDR can significantly impact the immune system by changing its balance, metabolism, and overall function. Immune cells have critical roles in combating infections as well as cancer prevention, and disturbances can result in autoimmune diseases. While many studies focus on higher doses of radiation, even low doses can alter immune health, as seen in various global reports. Understanding how LDR affects immune responses, especially in radiosensitive immune cells like T lymphocytes, is crucial for accurate health risk assessments.

T cells are vital for the adaptive immune response and are highly sensitive to radiation. Though changes in T cells are well-documented at medium or high radiation doses, there's a gap in our knowledge about how LDR affects these cells and immune responses. Therefore, our aim is to address the gaps in understanding LDR-induced immune alterations, focusing on T cell metabolic dysregulation, through a combination of well-controlled humanized and wild-type mouse models, immunologic studies, and integrative analyses “multi-omic’ datatsets that measure amounts and properties of genes, proteins and metabolites.

In this project, we focus on radiation doses of 10 cGy or less and use a multi-omics approach, which includes studying metabolites, gene expression, proteins, and epigenetic changes. Our previous research and preliminary data show that LDR can cause lasting molecular changes. Notably, we have shown that LDR does have measurable impacts on T cell metabolism and gene expression related to energy metabolism. We plan to use the animal models to examine the impact on T cell function in response to antigen challenge, and the effects on the thymus, which plays a pivotal role in orchestrating T cells’ maturation.

Our in-depth multi-omics approach will analyze changes in signaling pathways after LDR exposure. Metabolomics, which studies small molecules, i.e. metabolites, within cells, will be central to our research as it provides dynamic insights into how T cell function can be disturbed in response to LDR. This approach will complement other omics data and help us understand how genetic and transcriptomic changes lead to altered metabolic phenotypes and T cell immune responses. We will create a network map showing interactions between genes, proteins, and metabolites, which will serve as a resource for further hypothesis generation and integration with ongoing studies at DOE laboratories.

Our research has three main aims, each designed to provide a comprehensive understanding of how LDR impacts T cell function and overall immune health:

Aim 1: Deciphering thymus microenvironment responses to LDR in T cell maturation. This includes studying alterations in cellular composition, multi-omic profile, and molecular interactions within the thymus,an organ crucial for the development and maturation of T cells.

Aim 2: Examine LDR effects on mature T cell responses and assessing age-related impacts. This aim focuses on the effects of LDR on mature T cells, which are fully developed and actively participate in immune responses. We will assess how LDR influences T cell functionality, including their ability to respond to SARS-CoV-2 mRNA vaccination, which serves as antigens that trigger an immune response. Additionally, we will explore how these effects vary with age, given that aging can alter immune responses and increase susceptibility to radiation.

Aim 3: Multi-omic data management, integration, and interpretation. We will integrate findings from metabolomics, transcriptomics, proteomics, and epigenomics.Using advanced AI and machine learning techniques, we will create detailed maps of the molecular regulatory networks affected by LDR. These maps will illustrate the interactions between genes, proteins, and metabolites, providing a comprehensive view of how LDR impacts immune function. The integration of these multi-omic datasets will enable us to identify key molecular drivers of LDR-induced changes, offering new insights into the mechanisms underlying these effects.

Studying LDR is challenging because the molecular responses can be complex but subtle. Therefore, choosing the right model systems is crucial. Our planned studies on T cells are significant, as we've already observed clear responses within DOE’s preferred low dose range. Both short-term and long-term immune effects of LDR are relevant to human health, as shown in population studies. Our research will provide a detailed understanding of how LDR influences T cell development, functionality, and the broader immune system. This knowledge is crucial for developing accurate health risk assessments and for creating strategies to mitigate the adverse effects of LDR exposure on human health.

To maximize the utility of our data, we will make our multi-omic datasets publicly available, allowing for integration with other research programs like the Low-dose Understanding, Cellular Insights, and Molecular Discoveries (LUCID) program. All data and code will be publicly accessible to ensure reproducibility and to benefit the broader radiation research community.