The CDCN is excited to announce funding for four high impact research proposals! All four research proposals were submitted by expert collaborators of the CDCN and were provided grants of $42,000.
Functional Validation of Genomic Hits
The grants awarded to Drs. Byun, Ohgami, and Xiao will fund research investigating genetic variants observed in prior genetic sequencing studies of patients with Castleman disease.
The genetic code is the blueprint used by cellular machinery to produce the proteins that allow our cells to function. Variants in these genetic blueprints may lead to the production of faulty proteins that do not function correctly. Because many genetic variants are harmless, scientists perform functional validation studies to determine how a genetic variant impacts cellular functions and whether it is involved in a disease.
Prior research independently conducted by both Dr. Byun and Dr. Ohgami identified genetic abnormalities in the gene DNMT3A in select patients with Castleman disease. DNMT3A is of particular interest because it has been previously associated with diseases similar to Castleman disease, such as cancers of the blood. However, abnormalities in DNMT3A are also commonly found in people with no known disease. Drs. Byun and Ohgami will be using their grants to determine whether or not abnormalities in DNMT3A play a role in Castleman disease.
Using induced pluripotent stem cells, adult cells that are turned into a stem cell like state, Dr. Byun’s team will further explore their prior findings. "We performed whole-genome sequencing of patients with idiopathic Multicentric Castleman Disease (MCD). In one of the patients, an acquired mutation in DNMT3A gene was identified. The goal of this research project is to functionally characterize this mutation and to investigate the role of DNMT3A in the pathogenesis of idiopathic MCD with an emphasis on T cell biology."
Per Dr. Ohgami, his team will use their funding to perform laser microdissection to look for genetic variants in precisely selected lymph node cells. He hopes that this research will help to “identify and understand the neoplastic cell of origin in iMCD, and the dynamic relationship with the immune system.”
Previous work by Dr. Xiao identified a mutation in the MAP2K2 gene in a patient with the TAFRO subtype of iMCD. His team will use their grant to "study [whether] this mutation leads to increased production of cytokines that play an important role in the pathogenesis of this disease. Also, we will look for the specific cell type that has this mutation.”
While the previously identified genetic variants being studied now were not seen in all patients with Castleman disease, a validated genetic variant would be an important clue in unlocking the mysteries of the disease process. Such findings could allow for new diagnostic tools and targeted therapies in the future.
Identification of Cytokine Producing Cells
The last grant awarded by the CDCN will investigate cytokine producing cells in the lymph node tissue of patients with Castleman disease. Immune system hyperactivation and systemic inflammation in Castleman disease have been shown to be associated with increased levels of certain cytokines, such as IL-6 and VEGF; however, the cells responsible for increased production of these cytokines remain unknown. Dr. Vinodh Pillai and his team will be using their grant to pinpoint cells in lymph nodes responsible for producing specific cytokines using a technique called in situ hybridization. Identifying the cells responsible for cytokine production in Castleman disease is a critical step to understanding how the immune system malfunctions and could be used to identify new treatment targets.
To learn more about the CDCN's exciting research projects, check out our research pipeline!