Carol M. Artlett, M.D.; Drexel University College of Medicine; PRMRP Investigator-Initiated Research Award

Well, I research the disease scleroderma also called systemic sclerosis. And it's a disease that women get primarily. It's an autoimmune disease. And they get excessive collagen deposition in their skin and internal organs. Most people don't realize or make the connection that fibrosis versus chronic wounds are really two sides of the same coin. In the case of chronic wounds, you don't get enough collagen deposition. In the case of keloid scarring and scleroderma, you get too much collagen deposition. What we observed in diabetes is that they have decreased collagen expression and often that leads to chronic wounds. And so we're interested in the diabetic environment and how that's signaled in the fibroblasts. And the fibroblasts are what make the collagen. And what we wanted to do was to induce a pseudo-diabetic environment to the scleroderma fibroblasts to see if that down regulated collagen expression. And we found that a metabolite of glucose down-regulated collagen expression in the scleroderma fibroblast. In our research we've been using this compound, it's called 3-deoxyglucosone, and that's a metabolite of glucose. It's normally forming metabolite, but it's toxic to the body. And the body does all sorts of things to detoxify it. However, in the case of diabetes - where we see the decreased collagen expression, there is lowered ability to detoxify this compound. So from that we took the idea that 3-deoxyglucosone can down regulate collagen expression. And what we did was, we cultured scleroderma fibroblasts with 3-deoxyglucosone and the metabolites of 3-deoxyglucosone. And here we can see that this is our scleroderma fibroblasts without any treatment. And here with metabolites of 3-deoxyglucosone and 3-deoxyglucosone itself, we can see that the collagen mRNA levels are decreased. And when we looked at protein we also saw that the protein was decreased. So this got us really excited that perhaps we're affecting a pathway within the scleroderma fibroblasts that would enable the control of collagen expression. We looked at integrin receptors and integrin receptors communicate with the environment and the integrity of the collagen. So we wanted to see how were the integrin receptors expressed in scleroderma fibrosis given the 3-deoxyglucosone. And we saw that primarily there's a decrease in the beta 1 integrin. And beta 1, when it combines with one of the other alpha subunits, we see that technically there's a decrease in the integrins that bind collagen. And finally, as 3-deoxyglucosone is involved in diabetes, we have an inhibitor for 3-deoxyglucosone. And so what we wanted to do was see how it affected fibroblast migration into a wound site. What we see is a with 3DG collagen in a 48 hour period there is very little migration of fibroblast into the wound site where in as in a normal collagen matrices we see that wound is almost completely closed up. When you inhibit the 3DG formation with our compound called Dyn 15 you actually get increased wound closure and by 48 hours the wound is completely closed. This is very exciting--3DG is associated with chronic wounds in diabetes and yet we have potential therapeutic with this compound called Dyn 15 and it enhances closure rate of wounds. Scleroderma is a fairly rare disease, however as our population ages and more and more people go into the military particularly woman as they go into the military there is a higher incidence of Scleroderma within the veteran population. So this research has impact in many areas not only the diabetic area but the scleroderma area which I am particularly interested in but also chronic wounds.