Mitochrondrial Variance in Systemic Lupus Erythematosus: Understanding Mitochrondrial Regulations via Cytoplasmic Hybrid Cell Lines (CYBRIDS)
Abstract
Background: Systemic Lupus Erythematosus (SLE), often called lupus, is a chronic disease that occurs in young people in the prime of life. Lupus affects both young women and men and occurs in all genetic backgrounds, but is more common in women from puberty through into their 30s and is more frequently seen in people of African, Hispanic, and Asian descent. The patients affected by lupus are just starting their careers when afflicted by symptoms of severe fatigue, rashes, arthritis, organ failure (like kidney failure with dialysis), or death, thus limiting their productivity and lifespan. The underlying cause of lupus is not well understood, but it is known that ultimately, the immune system goes awry and attacks its own body. This immune reaction to oneself is called autoimmunity. Decades of research have looked at the genes and proteins that may cause lupus without conclusive results, but one part of the cell that has not been well studied are the mitochondria. The mitochondria are small pill-shaped components found in each cell and are often called the powerhouse of the cell, since they generate energy for the cell to work and, subsequently, for the body to function. More recent studies have shown the mitochondria are important in regulating the immune system. The mitochondria have their own DNA that is unique and works independently from the DNA found in the headquarters, or the nucleus of the cell. The reason for this is that the mitochondria came from rings of bacterial DNA that were adopted by the cell long ago, but are now essential to produce energy for cell survival. DNA sequencing is a method used to determine the lineup of the components that make up genes. The DNA lineup is different in each individual and as more is learned, it helps to explain the causes of some diseases. It is difficult to study the DNA of the mitochondria, but with newer methods that count and recount the genes components called Next Generation (Next Gen) Sequencing, it is possible to study variations in the genetic components of the mitochondria. One of the things that makes this study even more complex is that the mitochondria may change after birth. These changes are called somatic mutations, meaning that the DNA sequence is different from the inherited sequence. This is associated with certain cancers. Focus Area: Our initial studies suggest that somatic mutation also occurs in the mitochondria of patients with lupus. Understanding the genetic changes helps to know more about the pathways that cause autoimmunity in patients with lupus and why it is different in each person. One of the difficulties in studying mitochondria is that it is difficult to separate out the effect of the genes in the nucleus from those in the mitochondria. In this case, a special technique, cytoplasmic hybrid cell lines (cybrids), helps to separate the effects of the nucleus from the mitochondria, since the mitochondrial is removed and put into a cell without mitochondria whose nucleus is already defined. Thus, the effect from the mitochondria can be determined from each different person. This not only allows for better definition of what the mitochondria do, but in each patient with lupus, how the mitochondria behave and how this contributes to lupus. Potential Clinical Applications and Impact on Lupus Therapy: Cybrids provide a unique personalized system to see the effects of lupus in each individual patient. This will help to define what symptoms a patient will have, how their mitochondria respond to stress and how this affects their immune system and, most importantly, what medicines affect the mitochondrial function in each individual. Since the test is done in a test tube, the patient will better know if a medication will be helpful without having to take it and wait to see if it will help. Our goal is to identify the changes in the mitochondria in patients with lupus by comparing their Next Gen sequencing with healthy people of the same age,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910678
Entities
People
- Deborah Mccurdy
Organizations
- United States Army
- University of California, Los Angeles