Two early-stage projects targeting HIV and obesity advance with philanthropic support
Herman Fung wants to understand why genes turn on in some cells but not others, and how the on/off process is controlled. Linkang Zhou is curious about how tiny immune cells can clear enormous fat cells from tissue.
Both researchers are now launching projects to apply these basic science questions to public health challenges — HIV in Fung’s case and obesity in Zhou’s — with philanthropic funds from the U-M Life Sciences Institute.
The new projects were selected from applications for the LSI’s Klatskin-Sutker Discovery Fund award. In response to the numerous high-quality applications submitted this year, the review committee opted to divide the pool into tenure-track faculty and research scientists and selected one project at each level. As the tenure-track faculty recipient, Fung will be supported by the Klatskin-Sutker award. Research scientist Zhou will receive funding from a bequest to the LSI from U-M alum Dianne B. Segerstrom.
“When our family established this fund over a decade ago, our goal was to encourage high-risk, high-reward projects by funding that very early-stage work that has the potential to positively impact society,” Burton Sutker said. “It’s truly rewarding how many innovative ideas have emerged from this effort and how it is expanding to support even more approaches to solving important public health challenges.”
Exposing HIV’s hidden genetic stash
“HIV is a very tangible example of why it’s important to understand what makes genes active or silent in different cellular contexts,” said Fung, who is a research assistant professor at the LSI and assistant professor of biological chemistry and cell and developmental biology in the Medical School.
When the HIV virus incorporate its genome into human immune cells, it remains silent in some cells while activating in others. Those silent genes are the reason a permanent cure for HIV and AIDS has remained elusive. They create a hidden reservoir of viral genome that cannot be targeted or removed from the body, which can then reactivate in the future.
With the Klatskin-Sutker funding, Fung will probe what these HIV genes look like when they are turned on and off within the context of the cell. His lab is developing tools to label and pinpoint single genes within high-resolution images of the cellular landscape. Collaborating with Alice Telesnitsky, a professor of microbiology and immunology in the Medical School, his team aims to provide a proof of concept demonstrating how these tools can be applied to HIV.
“By actually seeing what the HIV gene looks like in an “on” state versus an “off” state, we can get a better picture of what factors contribute to these states,” Fung explained. “These results will lay the groundwork for longer-term efforts to perturb the active or inactive state in order to manage HIV more permanently and more effectively.”
Optimizing fat tissue’s clean-up crew
Under obese conditions, the primary cells in fat tissue — called adipocytes — enlarge as they store more fat. This expansion causes stress to the cell, eventually leading to cell death.
“So, you can imagine, something has to clean up these huge cells once they’ve died, to keep the tissue healthy,” explained Linkang Zhou, a metabolism researcher in Jiandie Lin’s lab at the LSI. “Otherwise, the dead cells become dangerous to the surrounding cells, causing issues like insulin resistance and diabetes-related pathologies.”
This clean-up task falls macrophages — immune cells that are hundreds of times smaller than the dead adipocytes they must remove. One way macrophages overcome this size barrier is by merging to form giant, multinuclear cells that can engulf the adipocytes.
Zhou studies how this merging process is controlled to promote balance within fat tissue. He and his colleagues have already identified one protein that is required for macrophages to fuse together: MS4A7, a protein that normally functions entirely within the cell. The team has demonstrated that mice lacking MS4A7 are unable to clear dead adipocytes as efficiently as wild-type mice.
With this new funding, Zhou will investigate how MS4A7 is involved in this merging process, and how it supports tissue health during weight loss induced by GLP-1 drugs.
“GLP-1 treatments can reduce fat tissue mass, but the tissue still needs macrophages to clear out dead adipocytes and reorganize the fat tissue to a balanced, healthy state,” Zhou said. “I want to test how activation of MS4A7 could be used to support this process. Is there a way we can make macrophage fusion more effective?”
To answer this question, Zhou will begin testing small molecules in search of a compound that can promote MS4A7 activity and, in turn, support the clean-up process within fat tissue both in obese conditions and during weight loss.