An Interview with Dr. Dana Graves on the Role of FOXO1 in Diabetic Patients
WCHM had the good fortune to land an interview with Dr. Dana Graves, who led a team of researchers investigating the FOXO1 molecule’s role in promoting healing in patients with chronic wounds and diabetes. We interviewed him about information on his recently published research. Dr. Graves is a professor in the Department of Periodontics, Vice Dean for Scholarship and Research, and Director of the Doctor of Science in Dentistry Program for Penn Dental Medicine under the umbrella of the University of Pennsylvania. Penn Dental Medicine is an ivy-league institution with a deep history in forging precedents in dental education, research, and patient care.
WCHM: Dr. Graves, can you please tell us about your background and what led to your interest in mucosal wound healing and diabetes?
DG: Well, I am a clinician. I am periodontist and I treat patients. One of the striking things about periodontal disease is that it is enhanced or increased by diabetes. Diabetes has effects on different tissues. As a periodontal surgeon, I place implants and perform surgeries where the wound healing response is impaired by diabetes. I became interested in the molecular mechanisms by which diabetes affects different tissues. I have studied bone as well as soft tissue healing, and I’ve been interested in how diabetes slows the healing process.
WCHM: Would you please explain your research of diabetes and non-healing wounds and your findings?
DG: In diabetes, a non-healing wound results from a number of events. In the early aspects, the wound heals slowly. A slower healing wound then can become colonized by bacteria, which sets up a non-healing situation. The aspect that I’m interested in is the initial aspect, which is the diabetic wound heals more slowly. I’m interested in why the wound heals more slowly, and I have not focused on the second aspect, which is why a slowly healing wound converts to a non-healing wound.
So think of it as two processes, and they’re linked together. The more slowly healing wound allows a situation to develop where the wound becomes colonized and doesn’t heal.
WCHM: What do your findings suggest is the link between FOXO1 and diabetes?
DG: We were originally examining FOXO1 in normal wounds. And we deleted the FOXO1 gene keratinocytes, which are the cells that form the outer layer of skin and are involved in closing the wound. The goal of wound healing is to close the wound as rapidly as possible. And the cells that are really essential for that are the keratinocytes, which are the outer layer. So we deleted FOXO1 in this particular layer of cells, and in the normal wound we found that when this particular gene was deleted, healing was much slower. This shows that the gene is needed because when it was removed, the healing got worse.
Then we found out what FOXO1 was regulating and we figured out the mechanism. I was then interested in finding out what might happen in a diabetic wound. So we created a wound on a diabetic animal and it healed more slowly, which is what you would expect.
Then we deleted the FOXO1 in the diabetic animal and the odd thing was that it speeded up healing. This was a real surprise. So you delete FOXO1 in the normal wound and it behaves like a diabetic wound. You delete FOXO1 in the diabetic wound and it behaves like a normal wound.
So it seems like this particular factor is a good factor in a normal wound but becomes a bad factor in a diabetic wound. The reason we say this is that when you delete this particular gene in the outer layer of cells, healing in the diabetic wound speeds up.
So our interpretation of this observation is that the FOXO1 molecule is interfering with healing because when you remove it, healing is faster and occurs at a more normal pace. What we then establish from this work is that FOXO1 plays an important role in promoting healing under normal circumstances, but in diabetic situations (or diabetic healing), this same molecule becomes a problem. So it becomes a “bad apple.”
WCHM: Can you talk about what these findings mean for the future of diabetes care?
DG: When you take a molecule that has gone from being a good factor to a bad factor, what you normally do is inhibit it under conditions where it’s harmful. This would suggest that if you can inhibit it in the diabetic wound, healing would be improved.
The next step is to try and develop a therapeutic factor. We have so far reduced the activity of the gene through genetic manipulation, so now we need to test what the impact of inhibiting it with a small molecule would be. These are experiments we have on the drawing board and will carry out very soon.
WCHM: I think you may have answered our next question. What are your future research plans for FOX01?
DG: The progression is to now perform experiments in a large animal model. We have established the concepts in mice and in order to do pre-clinical trials, we need to move in a larger animal. We plan to do these experiments in a larger animal to see if we applied this therapeutic factor, which is to inhibit FOXO1 with a small molecule, can we improve the healing environment for the cells.
WCHM: A number of our readers practice both wound care and hyperbaric medicine, so can you tell us a little about the impact your research findings might have on hyperbaric medicine in the future and how this could affect hyperbaric practitioners?
DG: Well, the link between FOXO1 and wound healing is pretty clear, and it is possible that there are links to the hyperbaric question you asked. How- ever, at this point they’re not known, and I wouldn’t be able to provide any real insight to that.
WCHM: Is there anything additional about your research and findings that you would like to address?
DG: Yes, well there is something that I think is quite interesting. It’s a bit technical. And that is when we looked to see what caused FOXO1 to change from being a good factor that promotes healing to a bad factor that inhibits it, we found that glucose itself caused that change. There is something about the high glucose environment that modifies the activity of FOXO1 which determines its particular consequences.
WCHM: Dr. Graves, if any of our readers would like to find more details or follow the research you’re doing, where can they get more information?
DG: They could look up my name, Dana Graves, in PubMed, which is a website run by the government that lists all the published articles. I have a follow- up study coming out in April in the Journal of Cell Biology that describes the impact on skin. So the first set of studies were on mucosal wound healing and the second set of studies, which we’ll publish in April, deals with skin healing. And I think that it’s interesting that this particular molecule FOXO1 is important to both types of wounds.
WCHM: Do you have any plans for presentations at upcoming conferences that you’d like to tell our readers about for anyone who might be interested in connecting with you personally and hearing more about your research?
DG: Yes, I’ll be presenting on this in the June 2015 Diabetes Conference in Boston.
WCHM: Dr. Graves, thank you for joining us today and sharing your research and findings with our readers. We look forward to connecting with you again and finding out more about your research and your future studies.
DG: Thank you very much for having me and having this discussion.
Dr. Grave’s article is published in Diabetes. Xu F, Othman B, Lim J, Batres A, Ponugoti B, Zhang C, Yi L, Liu J, Tian C, Hameedaldeen A, Alsadun S, Tarapore R, Graves DT. Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds. Diabetes. 2015 Jan: 64(1): 243-56. doi: 10.2337/db14-0589. Epub 2014 Sep 3.