The goal of our proposed study is to determine at the molecular level how a few select genes can convert human skin cells from patients into motor neurons, the nerve cells that are lost in diseases such as Lou Gehrig's disease. This approach has the potential to greatly accelerate our learning of why neurons die in these diseases because they can be generated from any individual with the disease and therefore allow personalized disease studies. This is critically important because many brain diseases have unidentified genetic causes, which makes the construction of animal models impossible. In addition, this procedure can be implemented for many patients in parallel, which greatly expedites research progress. The key to harnessing the power of this technology is to understand the precise nature of the nerve cells that it makes and learn how to modify the process to optimize the resulting neurons. By developing a deep understanding of how the conversion process works, we will help to deliver the benefits of this promising approach.
Statement of Benefit to California:
Neurologic disorders are among those that most commonly afflict Californians. Unfortunately, many of these diseases have been difficult to study because the genetic mutations that cause them are mostly unknown, making the construction of animal models impossible. Lineage reprogramming offers the ability to take skin cells from an individual with any heritable nervous system disorder and convert them into nerve cells in unlimited supply for laboratory studies. Critically, this allows the interrogation and testing of nerve cells that at least to some extent recapitulate the diseased state of the individual from which they were derived. Therefore, this approach could exponentially increase the types of nervous system diseases that can be studied by scientists. The key to harnessing the power of this system is to understand in great detail the molecular character of the nerve cells that are made and how to optimize the technique to improve them. Our proposal aims to do exactly this with the ultimate goal of bringing the full potential of this approach into clinical reality.