Leukemia, which is the leading fatal cancer of children worldwide, is among the childhood immunological diseases that may be influenced by the maternal environment. There is evidence to suggest that there are both genetic and environmental influences on the initiation and progression of disease.
To test whether inappropriate AHR activation during immune system development via the maternal environment has consequences for Notch signal transduction and Notch 1 dependent T-ALL, a combination of both in vitro and in vivo model systems will be employed. We will:
determine if AHR activation during fetal development, while nursing, or both, modulates disease penetrance;
identify potential changes in signal transduction cascades and epigenetic regulation that could account for the increased leukemia.
Initially, mouse fetal liver derived stem cells will be used, which has been shown to have long-term human translational potential in the fields of immunology and developmental immunotoxicology.
We would like to understand not only what are the underlying causes of a disease such as leukemia, and whether there ways to mitigate that risk. We propose to employ prenatal and/or lactational delivery of chemopreventative agent resveratrol in order to ameliorate the harmful effects of AHR activation. This study will be one of the first to test the efficacy of resveratrol when administered developmentally.
Identification of maternal environmental factors which affect the proper development and function of regulatory T-cells (Tregs) and TH17 cells is of critical importance and represents and area of research requiring a significant investment of ideas, models and energy. Cancer risk, atopic, allergic, and autoimmune conditions have been associated with developmental immunotoxicology, and a number of xenobiotics have been identified which affect maturation of Tregs.
EAE is an experimental model of multiple sclerosis, and coupled with a developmental exposure model, later life EAE induction represents an innovative approach to identify potential early life vulnerability windows critical for immune surveillance, inflammation and immune-mediated tissue injury. It also lends itself toward the study of the innate arm of the immune system.
Adaptation of an early life immune insult component to the EAE model to test questions about innate immunity, premits the broadening of this research into an area of developmental immunotoxicology that clearly warrants further investigation.