Pilot Study Using Intestinal Organoids to Test Whether Interferon-Beta Can Protect the Small Intestine in the Setting of GI-Acute Radiation Syndrome
October 21, 2024
A multidisciplinary research team from UPMC and the University of Pittsburgh was awarded a Pilot Grant from the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) Center for Medical Countermeasures Against Radiation (CMCRC) to study the “Use of Small Intestinal Organoids to Define Physiology of GI-ARS and Mitigation by IFN.”
Alison Kohan, PhD, FAHA, associate professor in the Division of Endocrinology and Metabolism and director of the Kohan Lab, is the project’s principal investigator.
Dr. Kohan is collaborating with two other investigators, including Joel Greenberger, MD, FACRO, FACR, FASTRO, emeritus chair and professor of Radiation Oncology and principal investigator of the University of Pittsburgh Center for Medical Countermeasures Against Radiation (CMR) and Amitava Mukherjee, PhD, research assistant professor in the Department of Radiation Oncology.
The study leverages Dr. Kohan's expertise in small intestinal epithelia and dietary fat transport in the body, in developing and using intestinal organoids and small animal models to better understand these processes, and that of Drs. Greenberger and Mukherjee, who study the effects of radiation on the human body and organ systems.
Their NIAID CMCRC-funded project will work to adapt the intestinal organoid system of Dr. Kohan’s lab to study the effects of gastrointestinal acute radiation syndrome (GI-ARS) on the intestine and whether the cytokine IFN-b affords protection against disruptions to small intestine function caused by radiation exposure – specifically, could the preservation of dietary fat absorption capacity by these cells be a critical aspect of the IFN-b mechanism of protection.
The research has potential application in developing future treatments for dealing with GI-ARS during a catastrophic nuclear or radiological incident, but also perhaps how to better protect the intestinal health and function in individuals who must receive radiation therapy as a part of cancer treatments.
"The GI tract is very sensitive to radiation," says Dr. Kohan. "In addition to cell death and associated events, we propose to test the possibility that loss of lipid absorption and metabolism capacity in response to a large dose of radiation is directly related to survival of the organism."
More Details About the Grant
The grant focuses on studying the effects of radiation on the gastrointestinal (GI) tract, specifically in the context of acute radiation syndrome. This condition can occur after exposure to high doses of ionizing radiation, such as in a radiological accident (e.g., the Chernobyl nuclear plant accident in the mid-1980s) or in a military conflict involving radiological agents.
Drs. Kohan, Greenberg, and Mukherjee are exploring whether IFN-b can mitigate the effects of radiation on the intestines by enhancing intestinal regeneration and maintaining chylomicron synthesis.
The research uses Dr. Kohan's organoid model to test the hypothesis that IFN-b can preserve or restore lipid absorption and intestinal viability after radiation exposure.
“This ability of IFN-b to offer some kind of protective effect on the intestine was something Drs. Greenberger and Mukherjee showed in their prior research using small animal models," says Dr. Kohan. "Of course, you can't study something like this directly in humans, which is why the organoid model is particularly suited to this kind of research."
The team's project will involve irradiating the organoid cultures at various doses to first determine the optimal dose and then understand its effects on chylomicron synthesis and other measurements.
Subsequently, organoid cultures will receive radiation doses determined from the first part of the study, be subjected to varying levels of IFN-b, [AF1] and be examined for chylomicron synthesis and function.
“What we’re trying to understand is if chylomicrons, or nutrient absorption in general, could serve as a benchmark for assessing GI injury following radiation exposure, and hopefully in future grants this physiology could then become a focus of acute treatment approaches,” says Dr. Kohan.
The Kohan Lab: Understanding Dietary Fat Absorption Mechanics of the Small Intestine
Dr. Kohan’s lab is focused on understanding how the small intestine absorbs, processes, converts, and transports dietary fats for use at the cellular level.
“The dietary fats we consume are typically in the form of triglycerides, which need to be absorbed and processed by the intestines to be used by the body,” says Dr. Kohan.
"This absorption process involves the formation of what are called chylomicrons, which are highly specialized particles synthesized by the small intestine that package and transport fats through the bloodstream.”
Dr. Kohan’s research is focused on two main objectives. The first is to understand the process of chylomicron formation by the cells of the small intestine. The second is to unravel the function and interactions of chylomicrons with other cells in the body once they are released.
"We follow chylomicrons wherever they end up in the body and try to figure out their mechanisms of action and function," says Dr. Kohan.
Prior work by Dr. Kohan and her lab has resulted in several significant discoveries in lipid metabolism and transport, including how a subset of proteins called apolipoproteins regulates these particles' metabolism. Her team’s work has shown that apolipoprotein C-III can impair the secretion of chylomicrons, which has implications for conditions like cardiovascular disease.
“A lot of our lab’s prior work has involved studies related to metabolic diseases and chylomicron function, but we’ve become interested more recently in how chylomicrons interact with the cells of the immune system,” says Dr. Kohan.
Dr. Kohan’s lab uses an array of investigative techniques, including intestinal organoids that can mimic the functional capacity of the small intestine. Her lab was the first to engineer primary small intestinal organoids for the study of dietary fat absorption (prior foundational organoid studies focused on stem cell biology and did not include nutrient absorption measures).
The use of intestinal organoids, created through the use of small animal models or human-derived tissue samples, allows her and her team to explore how chylomicrons interact with various cell types, including those of the immune system.
"Our lab also has been studying chylomicron formation in the setting of cystic fibrosis," says Dr. Kohan. "While CF is typically thought of as a lung disease, it has many other implications, one of which is malnutrition, which appears to be made worse by defective chylomicrons. So, we're interested in the many processes chylomicrons could be involved in throughout the body and whether chylomicrons could a new target to treat these diseases and improve human health.”
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