LSI faculty will explore new approaches to developing antiparasitics and preventing kidney disorders, with philanthropic funding
About a decade ago, Deborah Klatskin and Burton Sutker, M.D., along with their families, implemented their vision to invest in innovation at the University of Michigan Life Sciences Institute. Through a philanthropic gift, they established the Klatskin-Sutker Discovery Fund to fuel early-stage, crossdisciplinary research within the institute by providing seed funding for emerging concepts that have the potential to have a profound impact on human health.
Since then, the annual award has helped LSI faculty launch research projects to advance understanding of conditions such as Down syndrome and neurodegeneration, explore new hypotheses for the underlying cause of Huntington Disease, and develop novel molecules to target obesity, cancer, bacterial infection, and even SARS-CoV-2.
This year, for the first time, two projects have been awarded Klatskin-Sutker Discovery funding, marking the fund’s ninth and tenth projects to receive support from the endowed fund.
“It is deeply rewarding to know that our Discovery Fund is making a meaningful impact by supporting vital research that might not otherwise receive the attention it deserves,” Deborah Klatskin says. “We’re truly honored to be part of something so important.”
Engineering nature’s antiparasitic
In nature, microscopic organisms manufacture unique chemical compounds that allow them to survive, grow, and interact with each other and other species. In the LSI, biologist Filipa Barroso Pereira, Ph.D., uses systems and synthetic biology to coax these microorganisms to make new versions and greater quantities of their natural products, expanding access to chemical compounds that can serve as the basis for novel disease treatments.
In collaboration with the Sherman lab at the LSI, Pereira recently developed methods to engineer larger quantities and new variations of a natural product that was known to have anti-malarial properties. The latest versions she’s developed have shown promise in blocking malaria-causing parasites even more effectively than some drugs that are currently on the market.
While talking with Jay Brito Querido, Ph.D., a structural biologist in the LSI, she realized that this same compound may work on a related parasite that Brito Querido studies: Toxoplasma gondii, which causes toxoplasmosis and is associated with congenital birth defects and life-threatening diseases in immunocompromised patients.
Preliminary experiments revealed that the compound inhibits T. gondii. With the Klatskin-Sutker funding, Pereira is now exploring, at the cellular level, how the compound blocks the parasite’s ability to cause disease.
“As parasites evolve resistance to existing medications, the need for novel therapeutics becomes increasingly more urgent,” Pereira says. “With this funding, we can explore new potential drug activities and uncover the molecular mechanisms through which the compound inhibits these parasites. Once we better understand those mechanisms, we can apply that information to develop new compound derivatives and get closer to a new drug for patients.”
Probing proteins involved in kidney disorders
Within the kidney, specialized cells called podocytes line the blood vessels at the entrance to the organ’s filtration system. And within these cells, one protein appears to essential to keeping the kidney healthy. Swayam Prakash Srivastava, Ph.D., a cell biologist in the Inoki lab at the LSI, wants to figure out why.
The protein is called HECT type E3-ubiquitin ligase (HUWE1), and it is known to play a role in clearing unneeded proteins out of cells. Studies have found HUWE1 levels were significantly diminished in tissue samples from patients with various kidney disorders. Recently, Srivastava and Ken Inoki, M.D., Ph.D., demonstrated that a total loss of HUWE1 specifically in podocytes led to excessive protein accumulation in the urine and total kidney failure in mice.
“Loss of HUWE1 is related to many, many clinical symptoms of kidney disorders, so it is a very good target for understanding how to treat or prevent these diseases,” Srivastava says. “But we need to first find out how it is involved in podocyte health and the interactions between podocytes and other cells throughout the kidney.”
With the Klatskin-Sutker award, Srivastava will use several cutting-edge methods such as single-cell transcriptomics, ubiquitomics, and metabolomics to better understand HUWE1’s role in normal podocytes and other cells within the blood vessels. He also hopes to determine how loss of HUWE1 disrupts protein levels and which proteins are impacted in ways that lead to disease.
“HUWE1 is an essential protein for kidney health, but we know less about what it does in other organs like the heart and liver, for example,” Swayam says. “This study will not only enhance our understanding of how HUWE1 contributes to kidney health but also lay the foundation for exploring its role in health and disease in other tissues.”