Hear about Dr. Rangaraju’s American Brain Foundation-funded research and learn why better understanding the brain’s immune system can lead to treatments for brain diseases like Alzheimer’s.
At the American Brain Foundation, our philosophy of Cure One, Cure Many drives our efforts to support clinician-scientists working across different research areas. We believe that supporting early-career investigators is an investment in the brain disease treatments and cures of the future. Our Next Generation Research Grants are offered in partnership with the American Academy of Neurology in order to fund early-career researchers pursuing innovative research projects across the whole spectrum of brain diseases and disorders.
Srikant Rangaraju, MBBS, MS, received an American Brain Foundation-funded research grant in 2014 and has since received NIH grants in 2021 and 2022 to further his research. Dr. Rangaraju is an associate professor in the department of neurology at Yale University School of Medicine. In his previous position at Emory University, he established the Rangaraju Lab. The research group has since relocated to Yale University, and the team aims to develop a better understanding of how the brain’s immune system—including immune responses tied to a type of brain cell called microglia—contributes to the development and progression of neurologic diseases.
Dr. Rangaraju’s research is focused on developing new therapies that can be used to better control inflammatory immune responses in brain diseases like Alzheimer’s disease and stroke. We talked to Dr. Rangaraju about the importance of funding early-career research and the potential for treatments and findings about one disease to further our understanding of other diseases.
Dr. Rangaraju’s responses below have been condensed and edited for clarity.
Why were you inspired to study the brain?
Neurologic diseases disproportionately impact the lives of patients as well as their caregivers. When I was in medical school, we knew very little about how these diseases evolve, and there was a large unmet need for specialists in neurologic care. Within neurology, I was specifically drawn to stroke and Alzheimer’s disease, two major neurologic diseases that desperately needed effective treatments.
What specific issue is your research trying to address?
The brain’s immune system mainly consists of cells called microglia, which play an important role in how the brain develops and matures and become activated in the brain as we get older. Our research program is focused on how these elements of the brain’s immune response contribute to different neurologic diseases. For example, if microglial cells ‘over-respond’ to pathological proteins that aggregate in the brain, this can make matters worse by causing the loss of neurons and lead to cognitive problems. Our research focuses on the protein called Kv1.3, which partially controls how microglial cells respond.
What did your ABF-funded Next Generation Research Grant enable you to work on?
I was awarded the research grant in 2014, right when I finished my fellowship training. The grant provided me with ample time and some of the necessary funds to hire the personnel and carry out the research for my project. It had a significant impact on my research program because it allowed us to generate new data based on some preliminary experiments, which is critical to being competitive for larger grants, like those [I later received] from the NIH.
What kinds of insights or discoveries did this research lead to? What additional and/or current research did it enable?
For the American Brain Foundation grant, we proposed looking at brain tissue from patients who had passed from Alzheimer’s disease and brain tissue from mouse models to observe levels of the Kv1.3 protein. Was Kv1.3 truly present at higher levels in the brain tissue with Alzheimer’s disease compared to brain tissue that did not have disease? If we saw that, then it would provide a rationale for studying this further by blocking or targeting this protein in mouse models.
That hypothesis turned out to be true. Based on that success, we were able to secure career development awards and funding from the NIH to look at Kv1.3 blockers as potential therapies [for Alzheimer’s] in mouse models. That grant brought us one step closer to bringing some of these potential treatments and preclinical discoveries to patients.
What potential does this research into the brain’s immune response have for other disease areas?
There are many common aspects to immune system response, so understanding how the immune system or the microglia are important in Alzheimer’s disease and stroke can lead to therapies which can be potentially shared across multiple neurologic diseases. For example, if the mechanisms are similar between the delayed phases of ischemic stroke and Alzheimer’s and Parkinson’s, then treatments targeting those mechanisms can be used to achieve a beneficial effect across multiple diseases. Indeed, the Kv1.3 protein has turned out to be relevant to not just Alzheimer’s disease but also Parkinson’s disease and stroke.
What do you hope your research will do to help patients? How do you hope your research will help patients and their families?
We already have effective treatments for stroke, but they are focused on the very early window after stroke happens. We really don’t have treatments that can be effective after the first 24 hours. I’m hopeful that in the next decade, we will be closer to some immune-focused strategies to reduce the burden of stroke.
Additionally, I hope that in the next 10 years, we will have not just minimally effective but modestly effective treatments that can reduce Alzheimer’s disease progression.
If we were able to fund all of the research projects and areas of investigation we know are critically important today, how far along might we be?
I have been fortunate, but there are many researchers who have not been this fortunate, and that’s not for want of expertise or training. We lose a lot of highly skilled, very intelligent investigators because they’re not able to get funding at early career junctures. Additionally, the research money available is less than what is really needed to battle these diseases. If we had support for all the research projects looking to secure funding right now, I think we would definitely be closer to cures.
Why is it so important to fund research?
Funding is extremely important for research because it is the primary way in which new ideas can be developed and tested in the laboratory. This leads not only to new understandings of how brain diseases develop and progress but also to new drugs and treatments.
I’ll give one example from the stroke field. As of seven to eight years ago, the only major treatment that was available for the treatment of acute ischemic stroke—which happens when a blood clot blocks an artery and a part of the brain dies—was using “clot busting” medicines. These medicines are very time sensitive because you want to restore blood flow as soon as possible, so if they’re given too late, the damage is already done.
At first, we only had medications that could be given by vein for a handful of patients who were lucky enough to come to the emergency room in time. That has now transformed to very, very effective treatments where endovascular specialists can actually [insert a catheter] into the artery, grab hold of the blood clot, remove it, and restore blood flow immediately. This is way more effective than some of the purely drug-based therapies that are available for stroke. This has transformed the field—many more patients are now eligible for these treatments because they can be treated for up to 24 hours. These advances in stroke therapies would not have been possible without seed funding to support high-risk pre-clinical stages of research.
Through the American Brain Foundation, I’ve been involved in the review process for other researchers who are applying for Next Generation Research Grants. It’s wonderful to see many promising physician-scientists getting these grants and then following on to see how their careers have evolved just like mine has. Also, awards such as those from the American Brain Foundation can have catalytic effects on early careers of immigrant physician-scientists in the U.S., who are often not eligible for many federal grants.