Researcher Profiles
Aaron A. Hoskins, Ph.D.
University of Wisconsin-Madison
2023 Funding recipient
Leveraging Microfluidics and Biochemistry to Link DDX41 Genotypes with Molecular Phenotypes in MDS
Discovery Research Grant 2023
PROJECT SUMMARY
Co-PI with Polly Fordyce, Ph.D., Stanford University
Mutations in certain DNA genes greatly increase the risk of serious diseases like MDS or AML. Sometimes these mutations arise spontaneously in only certain cells (called somatic mutations), while other times these mutations are already present at conception and occur in every cell in the body (called germline mutations). One of the most commonly mutated genes associated with MDS/AML is DDX41. Hundreds of both somatic and germline mutations have been identified in DDX41. In fact, germline mutation of DDX41 occurs so frequently among MDS and AML patients that it is the most common genetic predisposition to these diseases. Despite its importance for MDS, we know little about how DDX41 functions or which mutations are least or most likely to change these functions. The goal of our research is to understand the fundamental biochemical and structural properties of DDX41. By understanding these properties, we hope that future MDS patients and those at-risk of developing MDS can be treated based on their individual DDX41 mutation and the specific defects in their protein that we uncover. To achieve this goal, we need to study DDX41 proteins with hundreds of different mutations that have been identified in humans so far. Until recently, this would have taken a team of scientists many years to complete. We can now do this in a matter of weeks by making use of break-through microfluidics technology. Microfluidics involves using small devices to conduct many biochemical experiments in parallel using very small volumes, dramatically speeding up that pace at which enzymes like DDX41 can be studied. In our experiments, we will use microfluidic reaction chambers that are so small that each can hold only 1/10,000,000 of a tablespoon and over 1,000 of them could fit on a postage stamp. By using these microfluidic devices, we can simultaneously study all of the DDX41 variants that have been identified in humans so far. In fact, we can even study the effects of mutations at every single amino acid in the DDX41 protein so that we can predict the consequences of mutations not yet discovered. When we complete our research project, our data will provide an invaluable resource for MDS patients and physicians by identifying which DDX41 mutations are least or most likely to disrupt protein function and revealing potential routes we could use to restore these functions. We believe that this will provide a new opportunity for treating MDS patients with different DDX41 mutations based on common defects in protein function and with drugs that restore these specific functions.