Generation of a Mouse Model to Investigate IL-6 Trans-Signaling in ALS
Abstract
Background: Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig s Disease, is a lethal disease that causes the death of spinal cord cells called motoneurons. Most ALS patients are diagnosed with the disease in their 50s after developing symptoms of muscle weakness, although the age of onset can vary from 20s to 80s. As the muscle weakness worsens over several years, the patient finds it progressively difficult to move their muscles all over their body, and eventually develops difficulty speaking, swallowing, and breathing. From the time of diagnosis, the average ALS patient dies within 2-4 years, with a majority of ALS patients dying of respiratory failure. Some ALS patients have genetic mutations that appear to cause their disease. However, in the majority of ALS patients, the cause of their disease is unknown. There are no cures for ALS, and in the past 22 years only two FDA-approved medications have become available to treat the progression and severity of ALS. There is an extreme need to identify medicines that can control ALS progression and thus prolong and preserve a higher quality of life for ALS patients and their families. When new medications are developed for ALS, new insights into how the disease starts and worsens over time can be developed. These new insights could help in developing a cure for ALS. Target of Study: Interleukin 6 (IL6) is a protein called a cytokine. When the body develops inflammation, for example, from an allergic reaction, the body produces high amounts of IL6. Thus, IL6 is one of the most important markers of disease, including ALS. However, high levels of IL6 can have detrimental effects on cells during chronic inflammation, leading the cells to change their size, shape, and function. IL6 does this by combining with a protein called a receptor (IL6 receptor) located on the surface of cells. Normally, only cells that have IL6 receptors can respond to IL6. This type of cell signaling is normal. However, when the IL6 receptor breaks off a cell, it can combine with IL6 and trigger abnormal signaling in cells that do not normally have IL6 receptors. This process is called IL6 transsignaling and is a process associated with a number of diseases like arthritis and cancers. IL6 has good and bad properties in the body depending on what types of cells are affected by IL6 signaling. In humans, the amount of IL6 transsignaling can be regulated by a mutation in the gene that makes the IL6 receptor. This mutation causes the IL6 receptor to break off of cells at increased levels; thus, this mutation makes IL6 transsignaling occur at higher levels in people who inherit this mutation. We believe that in patients who have this mutation in the IL6 receptor, IL6 transsignaling can make ALS progression more rapid or can increase disease severity depending on where it is occurring, such as in the spinal cord or at the muscles. Goal of the Study: In this study, we are proposing that IL6 transsignaling plays a role in making ALS progression and severity worse. Based on our early study, we also propose that ALS patients that inherit the mutation in the IL6 receptor gene may develop ALS that progresses faster and is more severe. However, this phenomenon is difficult to study in patients with ALS because IL6 transsignaling occurs in multiple areas affected by the disease and whether the effect is beneficial or detrimental at a specific area is not known. Thus, we propose to use an existing mouse model of ALS, called the SOD1 mouse, that represents patients who do not have the IL6 receptor mutation. To study how patients who have the mutation have worse disease, we propose to build a mouse model of IL6 transsignaling by modifying the IL6 receptor in the mouse and then breeding this mouse with the mutated IL6 receptor gene (Il6raSec mouse) with the SOD1 mouse. By developing this hybrid Il6raSec x SOD1 mouse, we will be able to measure the effects of IL6 transsignaling on the progression and severity of ALS by dete
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810377
Entities
People
- Gregory Hawkins
Organizations
- United States Army
- Wake Forest University