“ Being a Tullie and Rickey Families SPARK awardee was an amazing experience. My award gave me the freedom to test high risk ideas and we were rewarded with an important discovery that could lead to promising therapeutics for cardiovascular disease. No other program I’m aware of gives this freedom to post-doctoral researchers like myself. These awards truly have the power to boost high impact discoveries and careers.”
We are what we eat… macrophages can smell this and drive heart disease
FUNDED: JANUARY 2019
FUNDED BY: The generosity of the LJI Board Director Tom Tullie and the Tullie Family Foundation and various 2018 SPARK donors.
What was the goal of your SPARK project?
One in four Americans will die from the consequences of atherosclerosis, the buildup of plaques of fat and cholesterol in the arteries. The development of atherosclerosis is strongly affected by what we eat. The bacteria in our intestine eat with us, and some of the metabolites they produce when we eat a western style diet are associated with atherosclerosis progression. Our lab has discovered hundreds of olfactory receptors expressed in specific immune cells called macrophages (big eaters) isolated from atherosclerotic aortas of mice fed with a diet similar in composition to western food. Macrophages are important immune cells because they serve as the first line of defense, protecting the body from bacteria, viruses and cancer cells. They are also the primary contributors to atherosclerosis, the cause of heart attacks and strokes. I investigated how these olfactory receptors might activate macrophages in response to diet-induced volatile compounds.
SPARK project results:
Thanks to SPARK support, I confirmed the importance of olfactory receptors, in mediating the function of macrophages in response to diet-induced volatile compounds. This finding was novel, and in fact, I’ve worked with LJI’s Technology Development team to create an initial filing for intellectual property related to this discovery. The first screening of olfactory receptor function showed that seven olfactory receptors were able to induce inflammation. One particular receptor stood out: Olfr2, which acts as the receptor for octanal. Octanal, a diet-induced compound, can be detected in the blood of mice and humans—and can increase three times when the mice are set on a high-fat diet, similar to a typical western diet. Interestingly, we found that mice given high doses of octanal had a substantial increase in atherosclerosis plaque progression. I discovered that we could reduce inflammation and protect mice from atherosclerosis by blocking the receptor for octanal with a chemical inhibitor, or by modulating its expression with genomic editing techniques. These data give us a promising path for drug development to prevent and treat atherosclerosis- based cardiovascular diseases. This work also answered questions about the basic biology of olfactory receptors and the work in mice appears to be very relevant in humans. I discovered that the human octanal receptor, called OR6A2, functions similarly to the receptor in mice, inducing inflammation in response to octanal. Finally, some olfactory receptors, including the receptor for octanal, are expressed in certain white blood cells in humans. These cells can be incorporated in atherosclerotic plaques.
What’s next for this project?
Thanks to additional funding from Kyowa Kirin Pharmaceutical Research to help us expand our screening to more receptors, I’ve been able to keep working on this project in 2020. I am now using new technology called Rhapsody to help retrieve important data as we interrogate hundreds of genes across tens of thousands of cells purified from the blood of healthy donors—before and after eating a western-style high fat breakfast. This approach should shed light on which Olfrs change during high-fat food consumption and how these Olfrs influence human immune cells. Going forward, I plan to use single cell technologies to connect Olfr expression with how these receptors function in cardiovascular disease progression. My aim is to figure out how Olfrs are activated and uncover pathways involved in the initiation of inflammation in atherosclerosis. I also hope to extend this study to patients with cardiovascular disease by securing additional support for this project, and am actively seeking funding for this.
What’s next for Marco?
In October 2020, I applied to the NIH Pathway to Independence Award (K99) which is meant to help outstanding postdoctoral researchers transition in a timely manner to independent, tenure-track or equivalent faculty positions. In that application I was able to reference my work and experience from my SPARK project as an example of my ability to lead independent research. If successful, this grant would also help me continue my work on this project. My hope is that I will secure this K99 award or secure additional private funding to continue my research and ultimately help with my goal of transitioning to a faculty position in a couple years.