Investigating neuroimmune influences in neurodegeneration through Cas13d-based genetic interactions screens
In the United States alone, an estimated 6.9 million Americans live with Alzheimer’s Disease. This is thought to grow to 13.8 million by 2060. Understanding what causes Alzheimer’s Disease and other neurodegenerative diseases and how it progresses is key to developing therapeutics to prevent it.
Recently, the importance of the immune system in brain health has come into light. As people age and cardiovascular health declines, cells from the immune system, called T cells can infiltrate into the brain and wreak havoc on the cellular neighborhood. One way that can occur is that the T cells directly harm the neurons, which are the cells that communicate with each other in the brain. Another way T cells are thought to contribute to disease is through interacting with cells called microglia, known as the surveillance cells of the brain.
We want to address two questions. The first is what happens to T cells in the brain after they infiltrate? To address this, we will first study how T cells change when they encounter inflammation or brain debris. Next, we will turn off different genes associated with inflammatory response in T cells and see how they respond. Finally, we will analyze which combinations of genes drive harmful T cell behavior in Alzheimer’s disease.
Our second question is how do T cells affect microglia? We will first examine how microglia respond at the genetic level after being exposed to different T cells that have experienced different stimuli. Then, we will turn off different genes in microglia and test whether the changes make them more or less helpful to nearby neurons. By performing these experiments, we can assess the importance of pathways that we perturb on neighboring cells.
Through our research, we hope to gain more understanding of how the immune system and the nervous system interact to trigger neurodegeneration and develop potential therapeutics to prevent the death of brain cells.
