Genetics and the Environment: Evaluating How Maternal Dietary Exposure Affects Neurodevelopment and Cognition in NF1
Abstract
Rationale: Neurofibromatosis type 1 (NF1) is a genetic disease caused by mutations in the NF1 gene that affects 1/2,500 people worldwide. Up to 80% of children with NF1 suffer from cognitive manifestations, such as problems with attention, executive function, learning, and motor learning. The treatment options for NF1-associated cognitive deficits are very limited, and the underlying mechanisms remain incompletely understood. In addition, cognitive issues in NF1 display significant clinical variance, and the confounding factors (genetic and environmental) are poorly understood. Oligodendrocytes are cells that provide insulation (the myelin sheath) to neurons to facilitate fast neuronal communication and are required for healthy brain function. Oligodendrocytes are constantly being made from oligodendrocyte precursor cells (OPCs). Our preliminary data show that the Nf1 mutation results in abnormal patches with hyperdense OPCs that are impaired in making oligodendrocytes, leading to disrupted cognitive function. In addition, we showed that maternal obesity (a nutritional/environmental modifier) and its associated interleukin-6 (IL6) elevation causes increased OPC abundance early in development, suggesting that modifiers such as maternal obesity could interact with the Nf1 mutation to induce or exacerbate neurological issues in NF1. Objective: In this study, we propose a series of experiments designed to determine the interaction between Nf1- mutation and maternal dietary exposure (high-fat-high-sugar diet). We propose to determine whether maternal obesity exacerbates Nf1-related anomalies in OPCs (Aim 1), oligodendrocyte production (Aims 1-2), and cognition (Aim 2). We will also determine the role of IL6 by inhibiting the function of its receptor (Aims 1-2). Our proposal addresses two of the areas of focus in the 2022 DOD NFRP IIRA: Non-tumor manifestations (cognitive manifestations) and Nutritional, environmental, and other modifiers of NF1. What Types of Patients Will It Help and How Will It Help Them? The experiments proposed herein will help patients with NF1 by evaluating how two genetic and environmental factors (NF1 mutation and maternal obesity) affect cognitive symptoms and determine whether there is an interaction between these factors. This study is relevant to the clinical heterogeneity of cognitive phenotypes in NF1 and provides the initial proof-of-concept studies that environmental exposure may modify NF1-associated phenotypes to worsen cognitive deficits. What Are the Potential Clinical Applications, Benefits, and Risks? The experiments proposed will determine whether maternal obesity-induced IL6 elevation worsens NF1-associated cognitive deficits. This will help lay the groundwork for interventional studies to determine whether IL6 receptor (IL6R) inhibition (e.g., tocilizumab, FDA-approved) improves cognitive manifestations in individuals with NF1. Potential risks of treating pregnant women with IL6R inhibitors would need to be carefully studied in the future prior to implementation. What Is the Projected Time It May Take to Achieve a Patient-Related Outcome? This study will provide a potential rationale for further human investigation. These investigations could involve the correlation of maternal and/or childhood serum IL6 levels with imaging abnormalities or cognitive deficits in NF1. Such a study would provide additional rationale for trialing IL6R inhibitors in patients with NF1. The projected time of this project together with the follow-up human investigations may take 5-10 years. What Are the Likely Contributions of the Proposed Research Project to Advancing the Field of NF Research and/or Patient Care? Successful completion of the proposed studies will advance the field by deepening our understanding of how Nf1 mutation interacts with environmental/nutritional factors to induce cognitive impairments. Our studies will provide a rationale for further identifyi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310239
Entities
People
- Yuan Pan
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army