Congratulations to Ying “Maggie” Chen, MD, PhD, Assistant Professor of Medicine, Nephrology, who was awarded a $1.8 million grant (total cost) from the U.S. Department of Defense for her study “Development of Novel Podocyte Endoplasmic Reticulum (ER) Calcium Stabilizers to Treat Focal Segmental Glomerulosclerosis (FSGS).”
FSGS is the most common primary glomerulopathy leading to renal failure and disproportionately affects African-Americans, a highly represented population among military personnel and Veterans.
While it is known that podocyte ER stress plays an important role in the pathogenesis of FSGS, there is no treatment to date that targets podocyte ER. Currently, the mainstay of treatment for FSGS is immunosuppressant therapy that does not act on podocytes; in addition, these drugs do not halt disease progression in all patients and they have many adverse side effects.
“The ultimate goal is to develop a new class of drugs – podocyte ER calcium stabilizers – in the treatment of FSGS,” says Dr. Chen.
In previous studies, Chen’s team demonstrated that the podocyte ER calcium release channel, type 2 ryanodine receptor (RyR2), underwent a remodeling during ER stress, resulting in ER calcium leakage and cytosolic calcium elevation. The leaky RyR2 activated cytosolic protease calpain 2, which lead to podocyte injury. Importantly, they also identified a novel chemical compound (NCGC003844) that stabilized the podocyte ER RyR2. In other studies, Chen and colleagues were the first to report that MANF (mesencephalic astrocyte-derived neurotrophic factor) is a urinary biomarker of ER stress-related kidney diseases and that MANF has protective and immunomodulatory effects by inhibiting leaky podocyte RyR2 and attenuating calpain 2-caspase 12 activation in ER-stressed podocytes. As well, they have identified a candidate MANF receptor.
“Our research findings will define heterogeneous FSGS patients based on underlying molecular mechanisms,” says Chen. “The proposed therapies are pioneering ‘proof-of-concept’ studies that could lead to a significant leap forward in the treatment of military personnel.”
Chen is the recent recipient of a 2-year, $300,000 Mallinckrodt Challenge Grant for her study titled “Targeting Podocyte Dysfunctional Ryanodine Receptor to Treat Nephrotic Syndrome.” The grant was provided through a partnership between Mallinckrodt Pharmaceuticals and Washington University School of Medicine. Her group was one of six Mallinckrodt-awarded teams who presented their work at the Mallinckrodt “Science Day” event held November 12, 2019. Additionally, Chen has been awarded an Investigator Matching Micro Grant funded by WashU’s Center for Drug Discovery for development of a novel biotherapeutic protein to treat ER stress-mediated kidney disease.
Chen and her team have also pioneered the development of urinary ER stress biomarkers. She and colleague Yeawon Kim received a U.S. patent for their discovery of noninvasive biomarkers that have the potential to help diagnose certain human kidney diseases in their earliest stages of development. The co-inventors were honored at the 2nd Annual Celebration of Inventors, an event sponsored by the Office of Technology Management.
Read more about Dr. Chen’s research on the Y. Maggie Chen Lab website.