He may be a young investigator, but Mohamed Noureldein, Ph.D., has already had quite the globetrotting career. From his beginnings in Cairo, Egypt, then moved east for his doctorate work at the American University of Beirut, during which he was part of a science exchange program with Denmark’s Aarhus University. In 2021, he crossed the Atlantic to join Eva Feldman, M.D., Ph.D., and the NeuroNetwork for Emerging Therapies.
Fast forward a couple later, and he is now looking towards a new journey, having just received a K99 “Pathway to Independence Award” from the National Institutes of Health (NIH), which will allow him to establish his own lab in just two years. To top things off, Dr. Noureldein received the grant on his first try, a very rare feat.
“When I met Mohamed a few years ago, I was instantly impressed by his innovative thinking in his approach to research combining bioinformatics and genetics. I knew I wanted him to work at the NeuroNetwork,” explained Dr. Feldman. “Since he arrived in Ann Arbor, he has had an incredible impact on our research, not only through his own efforts, but by sharing his knowledge in transcriptomics and RNA sequencing to further other projects.”
To celebrate, and learn more about his exciting work, we sat down with Dr. Noureldein.
Tell us about your research.
The NeuroNetwork lab as a whole has been studying metabolic syndrome and its neurologic complications. I am particularly interested in how metabolic syndrome can lead to dementia. When you hear about metabolic dysfunction, usually your mind goes to fat and energy supply to muscles. An even larger issue is the effect it has on the energy supply in the brain. Why? The brain consumes more energy than any other organ in the body. In fact, 25% of all the energy you are using each day is used by the brain. So, you can imagine that when the energy supply is disrupted, the effects on the nervous system (including the brain) are immense, causing neurologic disorders that affect how the brain functions, disrupting cognitive functions, and leading to dementia. I want to understand how this energy is coordinated inside the brain, especially when metabolic dysfunction is present.
Is this the work the K99 will fund?
Yes, but it goes much deeper … let me explain. There are many types of cells inside the brain. There are of course neurons, whose job it is to do the processing for the brain, but there are also many supportive cells. I focus on one of those, oligodendrocytes.
Most of the attention to oligodendrocytes has been on their role in providing myelination, or insulation, for the axons and neurons. However, they also provide neurons with their fuel in the form of an energy substrate called lactate. Particularly I am looking at the shuttling of energy substrates from oligodendrocytes to neurons, which is affected by metabolic syndrome. My hypothesis is that when this lactate shuttle is disrupted in metabolic syndrome, neurons won’t be supplied with enough energy, which will lead to dementia.
My goal is to fully understand this mechanism and how it is affected in metabolic syndrome because that will give us the potential to target it with therapy. If we can rescue this pathway, then we are going to be able to rescue the neurons.
It’s early, but what have you learned so far?
First, we saw in cell culture (a petri dish) that neurons are very sensitive to any changes in energy substrate (how they get energy) and any changes in metabolism. So, when we mimicked metabolic syndrome by the addition of one of the fatty acids to the cells, we noticed that it disrupted both, causing the neurons to develop insulin resistance and die. When we treated oligodendrocytes (supporting cells), they required much higher concentrations of fatty acids to decrease function, develop insulin resistance, and so forth. This confirmed that oligodendrocytes are more resilient than the neurons themselves, so would require much harsher metabolic conditions to be affected.
Second, when we looked at the gene expression of one of the transporters carrying the lactate energy substrate to the neurons in a pre-clinical model that was fed a high-fat diet, we found something very interesting. This transporter was initially up-regulated, meaning there was an increase in gene expression when the pre-clinical model is fed a short-term high-fat diet. When we waited a much longer time (24 weeks) and looked at the same transporter’s gene expression, it was actually downregulated, meaning it had been compromised and was now under-expressed. This was exciting because it confirmed the hypothesis that the lactate shuttle tries to rescue neurons early on in metabolic syndrome. However, in chronic metabolic syndrome, it is compromised, so dementia will develop.
Finally, we have done some single-cell RNA sequencing to study the oligodendrocytes inside the brain. Until now, they have been considered a homogenous population of cells, meaning there is only one cell type. We isolated mature oligodendrocytes, and when we performed single-cell RNA sequencing, we actually found out that there were three different types of mature oligodendrocyte cells, each with a different function and a different gene expression signature.
We saw that one of these types, which we designated as “oligodendrocyte cluster two,” was more greatly affected by high-fat diet feeding than the others. It actually changed its function to mainly provide metabolic support to neurons in this high-fat diet condition. This is an amazing discovery. It really opened out thinking into the function of lactate shuttling.
So, when we performed sequencing on a high-fat diet and healthy pre-clinical models, we found that oligodendrocyte cluster two had a different functional expression in metabolic genes in the high-fat models compared to healthy ones. This was amazing because what it means is that some of the oligodendrocyte cells are actually repurposing their functions to provide mainly metabolic support to neurons in high-fat diet conditions. This really opened our thinking into the function of lactate shuttling, how energy substrates are shuttling between oligodendrocytes and neurons, and how this can be a mechanism before that dementia associated with metabolic syndrome so we can target it.
You were studying in Cairo and then Beirut. What brought you to the U.S. and the NeuroNetwork for Emerging Therapies?
Towards the end of my Ph.D. work under the mentorship of Assaad Eid, Ph.D., in Lebanon at the American University of Beirut (AUB), Dr. Feldman came to visit us since both she and Dr. Eid were studying diabetic complications. During a gala dinner, she gave a talk about her work. Her use of transcriptomics, RNA sequencing, and genomics really piqued my interest.
Then during an outing, I had a chance to speak with Dr. Feldman one-on-one and told her about my own work in diabetic complications using genetics and bioinformatics. Apparently, she thought my work was equally interesting, because during our follow-up talks, she asked if I would be interested in doing postdoc work with her, and the rest is history.
Everything moved pretty fast, compounded by the fact that this is your first time in the U.S. What was that like?
I was intimidated at first by moving to a new field, in a new lab, and in a new country. While my work is still in the realm of diabetic complications, I am now exploring the brain and nerves, which was very new to me. I had studied them in courses but hadn't done any research on them.
Luckily, I had support from the entire team here. They are all excellent collaborators and are my teachers. Their help allowed me to switch to the brain by helping me lay the foundation, especially Sarah (Briskin Emerging Scholar Sarah Elzinga, Ph.D.) who is working on similar research. She has been amazing and did so much to ensure that I hit the ground running. I think that's why my first submission for the grant was like a second submission because I already had all her experience behind me. The support staff and technicians are amazing as well. I have learned so much from them and from the experience in the lab.
Now, having been here for a little while, was it what you expected?
Well … it was definitely very different from what I expected but in a really good way. When I was working in Lebanon, we always had trouble with getting supplies, receiving antibodies and biologicals, and dealing with the regulations. So, the first thing that surprised me was how everything moves so much faster here since many of the suppliers are local.
Secondly, I expected that everyone would be completely focused on their own project.
As I said before, the reality is the exact opposite. Everyone is very willing to help each other.
What has it been like working with Dr. Feldman?
That was another happy surprise. I knew it would be an incredible experience to have her as a mentor, but initially thought I would have to work relatively independently on my postdoc research. Of course, it is up to me to do the work, but Dr. Feldman is available all the time. She is very supportive, and she guides you the entire way. It’s a perfect balance of her letting you be independent and her supporting you and following your progress.
I never before in my entire academic career had weekly meetings with my advisors, but I have been doing so since day one here. This is very beneficial because it gives you an endpoint — you have your meeting, you are responsible for your project, and you will have her guidance and supervision following your progress. That's amazing.
Dr. Feldman always inspires us to be better and want more. I only applied for my K99 this soon because she pushed me. I started drafting the proposal last year, after only working as a postdoc for a little over a year. I thought, “Yeah, okay. I can do it, but I’ll never get it.”
I figured it was a way for me to get experience in applying for grants.
She actually believed in me, I think more than I believed in myself. Not only that, she helped me through the entire process.
How do you like living in Ann Arbor?
In short, I really like it. I'm very happy about working at the University of Michigan and living in Ann Arbor especially because I don't like big cities. I could never imagine myself living in Chicago or New York because I find it so crowded and stressful.
The University of Michigan and Ann Arbor also have diverse cultures and are very open to everyone. I was worried it would be the opposite, but I’m happy I was wrong.
Finally, it may sound simple, but I love walking to work every day. You arrive with your full energy. You haven't spent any energy or stress driving. Driving is crazy in Cairo where I am from. We also don't have many green areas and parks because it's an industrial city. I am happy with what we have here. We have parks everywhere and you see trees everywhere.
What are your thoughts on starting your own lab (the end result of the K99)?
When I got the word about receiving the K99, I was so happy at first. Then, like 10 seconds later, I was panicking. It’s only two years until you need to build your own lab. Two years in research is nothing, and then you must be completely independent. It's a huge step. But at the end of the day, of course, I am happy about it. Having people behind you, like Dr. Feldman and everyone from the lab, makes you feel like you can accomplish anything. There are also many people that have done it before. That’s what is amazing about Dr. Feldman’s mentoring legacy — so many people have gone through the same steps before, and are more than willing to help. So, I am putting my fears aside. I know it will be challenging at first, and it will be hard work, but when you like what you do and are passionate about it, the potential is really exciting.