Emery H. Bresnick, Ph.D.
2020 Funding recipient
Building an Interpretive Guide to MDS-Linked Mutations from Patient Clinical Data
Discovery Research Grant 2020
The Bresnick group conducts research on the development and function of blood cells that fight infection, protect cells and tissues by supplying oxygen and prevent lethal bleeding. These processes are studied in the contexts of physiology and the blood disease MDS. In MDS, the basic operating rules controlling the function of cells that produce blood cells, the stem and progenitor cells, become corrupted. Under the auspices of these corrupted rules, the cells malfunction, which causes deficiencies in the blood cells that are vital for life. To maximize the impact of our scientific and medical contributions and ensure that no barriers exist between our laboratory experimentation at the bench and the MDS patient in the clinic or the MDS-predisposed individual in the population, this proposal is a collaboration with physician-scientists that diagnose and treat MDS. Our outstanding physician-scientists reside at Dr. Bresnick’s institution (Jane Churpek and Inga Hofmann, UW-Madison) and other superb institutions (Lucy Godley, U. Chicago; Steven Holland, NIH, NIAID) and, in aggregate, create a highly interactive, multidisciplinary team.
This proposal relies on the core expertise of Dr. Bresnick’s group to understand how the human genome functions and how aberrations in the governing processes cause MDS. The application of clinical genetics to diagnose patients with blood cell deficiencies termed cytopenias regularly reveals changes in our genome – changes in single components of DNA termed nucleotides, or in some cases, more substantial changes to multiple nucleotides. These changes alter the fundamental chemical composition of specific proteins in the cell or the levels of the proteins and reconfigure principles dictating cellular behavior, e.g. whether cells divide, replicate, produce distinct progeny or die. By virtue of human genetic diversity, individuals harbor “genetic variants” or DNA differences within genes. On the surface, it might appear that a variant at a gene known to regulate blood stem or progenitor cells would influence blood cell development and function. However, a given variant may have little to no impact. A major challenge is to discriminate among the variants that increase the probability of developing MDS, cause MDS or have no impact. Establishing whether a specific variant predisposes an individual to “insults” that cause MDS, insults that originate from genetics or the environment, has enormous potential to prevent disease onset and even to reverse the course of disease progression.
Even those with the greatest human genetics expertise often cannot predict the functional consequences of certain changes in our genome. New technologies to manipulate genomes have unveiled unexplored avenues for deciphering normal and disease-linked genome structure. By focusing on two critical genes known to create an MDS predisposition, GATA2 and DDX41, we have devised strategies to surmount this critical problem. I envision that our studies will establish rules that enable the development of approaches to improve the diagnosis and prevention of MDS. Moreover, the mutant proteins generated by these genes in MDS may represent targets for therapeutic modulation, and therefore it is crucial to develop great expertise with the prospective targets.