Stem Cell & Regenerative Medicine members Feyza Engin and Ahmed Mahmoud have received the 2023-2024 University of Wisconsin-Madison Vilas Associates Award. This honor recognizes new and on-going research of the highest quality and significance. Those who are selected receive research salary support for summers 2023 and 2024, as well as a flexible research fund in each of the two fiscal years. A description of their research projects are outlined below.
Autoimmune disorders occur when the body’s immune system recognizes self as non-self and destroys healthy tissue. One attractive therapeutic intervention to combat this would be for the tissue to disguise itself from the invading immune cells and escape destruction. If this can be achieved transiently when immune cells are learning to be tolerant to self-tissue, it would be a mechanism to overcome autoimmunity.
More specifically, we are working to apply this to Type 1 Diabetes (T1D), which results from autoimmune-mediated destruction of insulin-producing beta cells and can occur at any age, with a peak in incidence around puberty. More than 2.5 million people in the United States live with T1D. We have previously shown that deletion of a stress response gene, IRE1, in pancreatic beta cells of a T1D preclinical model protects mice against diabetes largely due to a transient beta cell dedifferentiation. Transient dedifferentiation is a process of temporary cell fate reversal through the manipulation of gene regulatory processes and offers a novel, previously unexplored therapeutic intervention that could be broadly applicable to a large number of autoimmune disorders. The Vilas Associate Award will allow us to investigate the molecular mechanisms underlying transient beta cell dedifferentiation in IRE1-deficient T1D mouse model. To identify both differentially regulated genes and accessible regions that change in all the detected cell types during disease progression, we will perform combined single cell (sc) RNA seq (scRNA-seq) and sc Assay for Transposase-Accessible Chromatin (scATAC-seq) in islets. The results from this work will have the potential to lay the foundation for the development of groundbreaking therapeutic strategies for the prevention of T1D.
We have recently overcome a long-standing barrier to regrowing cardiac tissue after a myocardial infarction. We discovered that cardiac regeneration could be triggered in adult mice following cardiac injury by inhibition of the mitochondrial respiratory complex II succinate dehydrogenase (SDH). We showed that SDH inhibition stimulates adult cardiomyocyte proliferation, induces revascularization, and results in myocardial regeneration and restoration of cardiac function following injury. However, it is unclear which cell type(s) are primarily responsible for regeneration following SDH inhibition. In addition, the molecular mechanisms that regulate adult cardiomyocyte cell cycle re-entry, angiogenesis, and fibrosis resolution remain undetermined. During the Vilas Award, we will dissect the cellular and molecular mechanisms by which SDH inhibition metabolically reprograms the adult heart to a regenerative state. We will use genetic mouse models for cell-specific inhibition of SDH to identify the cellular mechanisms underlying this regenerative response. In addition, we will perform single cell analysis to define the transcriptional landscape of multiple cardiac cell types during SDH-mediated heart regeneration.