The Co-Laboratories Award is an internally funded award that encourages “start-up” collaborations and brings together researchers who have not worked together in the past. The award, which provides as much as $100,000 in project funding per year for up to two years, connects those who might not otherwise collaborate to investigate and attack diseases from many angles, drawing on the unique expertise of each researcher. This seed funding will provide the data researchers need to secure larger funds from external sources, like foundations and the National Institutes of Health.
Understanding the Epigenetics of Prostate Cancer
Prostate cancer is the second leading cause of cancer-related deaths in the United States. Prostate cancer cells’ ability to grow resistant to first-line treatments is the primary reason for this lethality. Once the cells adapt to evade treatment, they grow and spread unchecked. Hannelore Heemers, PhD, Department of Cancer Biology, and Byron Lee, MD, PhD, Cardiovascular & Metabolic Sciences, are teaming up to find new interventions that may halt this aggressive disease progression. Their collaborative research will focus on activities related to the NKX2-5 gene.
Similar to how a light dimmer reduces a light’s brightness, hypermethylation (chemical changes to regions of DNA) turns down NKX2-5 expression. This reduced gene expression results in dangerous changes to the shape and structure of prostate cells that promote aggressive cell behavior and lead to cancer. Drs. Heemers and Lee will investigate whether restoring normal NKX2-5 function can prevent prostate cancer progression. While most studies into prostate cancer progression focus on genetic targets, this co-laboratory project will focus on epigenetic factors that lead to disease.
Harnessing AI for Diagnosing Liver Cancer
As rates of obesity and diabetes continue to rise in the United States, so too has the prevalence of non-alcoholic steatohepatitis (NASH), now the leading cause of liver cancer. Currently, there are no drugs or interventions approved to halt or prevent this lethal progression.
A new research collaboration between Takuya Sakaguchi, PhD, Department of Inflammation and Immunity, and Daniel Rotroff, PhD, Department of Quantitative Health Sciences, will explore how genetics contributes to the progression of NASH to liver cancer. The research team will use a genome-wide association study approach to identify new genetic variants associated with liver cancer in zebrafish. Finding these variants is the first step to uncovering new disease-driving genes.
They also seek to develop a predictive model using artificial intelligence (AI) that can analyze histology images to detect early-stage liver cancer and predict treatment response. Incorporating AI into clinical diagnostics has been an emerging interest of the medical community. Drs. Sakaguchi and Rotroff are hopeful that this deep-learning model may one day be used in patient practice.
Combatting Transplant-Associated Pathogens
Transplant patients are particularly susceptible to infections from newly acquired or reactivated pathogens as a result of compromised immune systems. Patients who receive bone marrow or stem cell transplants, technically termed hematopoietic cell transplant (HCT), are particularly at-risk for reactivated human cytomegalovirus (HCMV), a common herpesvirus that lays dormant in 80% of adults, and HCMV-related diseases, which can result in death.
Christine O’Connor, PhD, Genomic Medicine, and Betty Hamilton, MD, Taussig Cancer Institute, are working together to understand how HCMV interacts with transplant patients’ immunocompromised systems to spur viral reactivation and infection.
In addition to studying host-pathogen interactions, they are in search of biomarkers that can signal which patients are most susceptible to HCMV reactivation and preventive drug targets as there are currently no treatments approved to prevent reactivation. To do so, the researchers will sequence patient and viral genomes to identify proteins and patterns that may help researchers and physicians determine predictive signatures.
Neuronal Dysfunction in Alcohol Abuse
Chronic alcohol exposure—whether from fetal exposure during development or binge drinking during adolescence and adulthood—impairs brain development and function. Research suggests that the brain's resident immune cells (called microglia) play an important role in this harmful process. As understanding of the microbiome and its importance to overall health has advanced over recent years, researchers from the Department of Inflammation and Immunity and the Department of Neurosciences wonder if gut-brain interactions may influence microglia's role in alcohol-related neurotoxicity.
Laura Nagy, PhD, and Dimitrios Davalos, PhD, will investigate using preclinical models and imaging technologies developed in Dr. Davalos' lab how increasing alcohol exposure affects the interactions between microglia and neurons (nerve cells found in the brain), and leads to neuronal dysfunction. They will go on to investigate whether preventing alcohol-induced loss of gut integrity using a therapeutic agent previously developed in Dr. Nagy's lab (hyaluronic acid, also called HA35) can curb microglial activation and subsequent neuroinflammation.
If the team finds that HA35 does in fact protect the gut and prevents alcohol-related neuroinflammation, there is great hope for rapid translation into clinical trials as HA35 is currently undergoing safety testing in healthy adults.
Smooth Muscle Hyperplasia in Crohn's Disease
More than half of all patients diagnosed with Crohn's disease (CD)—a chronic disease that causes inflammation and irritation in the digestive tract—present with intestinal strictures, or obstructed intestines. Most scientists have long assumed that immune cells are the central players in this process. Researchers from the Department of Inflammation and Immunity and the Department of Molecular Cardiology think there is another hypothesis worth investigating.
Florian Rieder, MD, and David Van Wagoner, PhD, have teamed up to uncover how fat cells may contribute to CD-related fibrosis and intestinal narrowing. The research team suspects that creeping fat contributes to the abnormal intestinal narrowing characteristic of CD by inducing smooth muscle cell hyperplasia (increased tissue mass due to cell proliferation). They hypothesize that alterations in free fatty acid metabolism drive this process.
The team will conduct a series of cell signaling and proteomic analyses in human tissues and cells to evaluate the direct and indirect interactions between fat cells and intestinal muscle cells. With a better understanding of how creeping fat contributes to intestinal obstruction, Drs. Rieder and Van Wagoner hope to identify viable therapeutic targets to prevent or treat intestinal stricture formation.