Public Abstract

DE-SC0025240: Human bone-Marrow model for response network studies of low dose / low dose-rate radiation exposures

Award Status: Active

Institution: The Trustees of Columbia University in the City of New York (Medical Center), New York, NY
UEI: QHF5ZZ114M72
DUNS: 621889815

Most Recent Award Date: 08/13/2024
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: Amundson, Sally

Supplement Budget Period: N/A

Public Abstract

Title: Human bone-Marrow model for response network studies of low dose / low dose-rate radiation exposure Sally A. Amundson, Columbia University (Principal Investigator) Aaron Viny, Columbia University (Co-Investigator) Guy Garty, Columbia University (Co-Investigator) Robert Ullrich, Columbia University (Co-Investigator) Kellie Machlus, Harvard Medical School / Boston Children’s Hospital (Consultant) Abstract: This project focuses on the radiation response of bone marrow stem cells, the target cell type for radiation-induced acute myeloid leukemia (AML). We will use flow cytometry to measure changes in cell type composition and differentiation, as well as generation of reactive oxygen species (ROS) after exposure to low dose (0, 10, 100 mGy) and low dose-rate (100 mGy at 5 mGy/h) radiation. We will compare the responses in 2-dimensionally cultured bone marrow stem cells and in a 3-dimensional organoid model that reproduces key elements of the bone marrow niche to support the growth and function of human blood-forming stem cells. We will also measure the changes in gene expression after low dose and low dose-rate exposures. In the 2D bone marrow cells we will use standard RNA-Seq. In the bone marrow organoids we will use single-cell RNA-Seq to assess changes in a cell-type specific manner and to investigate interactions between cell types. Comparing responses in the 2D and 3D models will help define the contributions of the bone marrow niche to radiation response. The organoid model can support the engraftment, growth and function of donor bone marrow stem cells, thereby letting us study conditions that may increase an individual’s sensitivity to radiation-induced AML. We will engraft the organoids with bone marrow stem cells from healthy donors or donors with a defined pre-leukemic condition, clonal hematopoiesis. We will again use flow cytometry to measure changes in cell type composition and generation of ROS in the engrafted organoids after low dose and low dose-rate radiation exposure. This project will provide: An organoid model that allows low dose / low dose-rate radiation experiments on the human bone marrow niche and target cells relevant for development of AML. Data on changes in cell types, ROS, and gene expression in bone marrow organoids. A model for the study of individual radiosensitivity. Insight into the pathway by which low dose radiation exposure can lead to the development of acute myeloid leukemia, to better understand radiation risks.

Title: Human bone-Marrow model for response network studies of low dose / low dose-rate radiation exposure

Sally A. Amundson, Columbia University (Principal Investigator)

Aaron Viny, Columbia University (Co-Investigator)

Guy Garty, Columbia University (Co-Investigator)

Robert Ullrich, Columbia University (Co-Investigator)

Kellie Machlus, Harvard Medical School / Boston Children’s Hospital (Consultant)

Abstract:

This project focuses on the radiation response of bone marrow stem cells, the target cell type for radiation-induced acute myeloid leukemia (AML). We will use flow cytometry to measure changes in cell type composition and differentiation, as well as generation of reactive oxygen species (ROS) after exposure to low dose (0, 10, 100 mGy) and low dose-rate (100 mGy at 5 mGy/h) radiation. We will compare the responses in 2-dimensionally cultured bone marrow stem cells and in a 3-dimensional organoid model that reproduces key elements of the bone marrow niche to support the growth and function of human blood-forming stem cells. We will also measure the changes in gene expression after low dose and low dose-rate exposures. In the 2D bone marrow cells we will use standard RNA-Seq. In the bone marrow organoids we will use single-cell RNA-Seq to assess changes in a cell-type specific manner and to investigate interactions between cell types. Comparing responses in the 2D and 3D models will help define the contributions of the bone marrow niche to radiation response.

The organoid model can support the engraftment, growth and function of donor bone marrow stem cells, thereby letting us study conditions that may increase an individual’s sensitivity to radiation-induced AML. We will engraft the organoids with bone marrow stem cells from healthy donors or donors with a defined pre-leukemic condition, clonal hematopoiesis. We will again use flow cytometry to measure changes in cell type composition and generation of ROS in the engrafted organoids after low dose and low dose-rate radiation exposure.

This project will provide:

An organoid model that allows low dose / low dose-rate radiation experiments on the human bone marrow niche and target cells relevant for development of AML.
Data on changes in cell types, ROS, and gene expression in bone marrow organoids.
A model for the study of individual radiosensitivity.
Insight into the pathway by which low dose radiation exposure can lead to the development of acute myeloid leukemia, to better understand radiation risks.