Research Profile

Diabetes results in high sugars that damage small blood vessels throughout the body. This can lead to dysfunction of multiple organs including the brain, eyes, heart, kidneys, and nerves. Proper small vessel function is critical for oxygenation and nutrient delivery. The mechanisms that drive small vessel damage are clearly complicated and incompletely understood. A significant barrier is cause by the complex organization of small vessels, which are made of two different cell types. Interactions between the two cells and the surrounding tissues are critical to disease pathogenesis and new disease models that capture these interactions are clearly needed. This proposal describes a plan to develop a microfluidic platform that incorporates human blood vessel cells that self-assemble into perfusable small vessel networks for modeling diabetic small vessel disease outside of the body. The specific aims are: 1) to develop, characterize, and utilize a microfluidic model of diabetic small vessel disease and 2) to utilize gene expression and protein analyses to investigate pathogenesis and to identify new biomarkers to track the progression of diabetic small vessel disease. In addition, advanced microscopy and biochemical assays will be used to characterize morphology, function, and signaling pathways in our temporally and spatially controlled system. Completion of the study proposed will increase understanding of the biological processes driving diabetic small vessel disease, generate new biomarkers to track disease, and establish a platform to potentially test new therapeutics.

Diabetes results in high sugar levels that can damage the small blood vessels throughout the body. This can cause dysfunction in multiple organs including the brain, eyes, heart, kidneys, and nerves. The mechanisms that cause this are complicated and incompletely understood. Animal models are expensive and may not accurately represent how human cells respond to high sugars, and human studies are even more costly and challenging. New disease models are clearly needed. Ideally, such platforms would utilize human cells that could maintain their normal 3D orientations, could be grown and maintained outside of the body and be easily visualized. In preliminary experiments, we have been developing lab-on-a-chip technologies that incorporate human blood vessel cells which self-assemble into perfusable microvascular networks on small devices that are maintained outside of the body. We believe that this is an ideal system to study the effects of high sugar on the cells within the small vessels and their surroundings. We will use advanced microscopy techniques, biochemical assays, genetic manipulations, advance gene sequencing, and protein analyses to investigate how high sugars affect cells and their interactions with other cells and their environment. Completion of the study proposed will increase our understanding of and ability to track diabetic small vessel damage and will help us rationally design and test new therapeutic approaches in the future.

I still vividly remember one of the first patients that I saw in clinic as a medical student more than 15 years ago. He was a patient with diabetes who had many of the complications that our research is trying to understand better. He had damage to his eyes, nerves, and kidneys as a result of small vessel disease induced by diabetes. I remember being shocked by how high sugars could cause so many different problems throughout the body. Over the years, I have taken care of many patients with diabetes. I have seen them in the intensive care units, on dialysis machines, in medical units, and before and after lower extremity surgical amputations. It is clear to me that a better understanding of how diabetes causes small vessel disease is needed so that new therapies can be developed to combat this terrible disease. As someone what has been trained as a physician and a scientist, I know that more research is needed. I feel that the technologies that we have been researching and developing can be used to significantly advance our knowledge of diabetes and ultimately improve medical care of patients. This American Diabetes Association grant funding will be essential for my team and I to continue to explore and develop our tissue engineered platform designed to investigate how diabetes damages small human blood vessels and leads to multi-organ damage. It will also facilitate networking and collaboration with other diabetes researchers that could help all of us make even progress in a synergistic manner.

So much amazing research as been done in the field of diabetes in recent years. The engineering of the insulin pump has been an really important for patients as well as clinical research showing the benefit of drugs like the SGLT2 inhibitors and GLP-1 agonists. Looking ahead, there are so many exciting directions for the future of diabetes research. New drugs targeting immune cells could have the potential to prevent the progression of type 1 diabetes. In tissue engineering, I anticipate that microfabrication of miniature micro-electromechanical systems (MEMS) will be an important area of research where human disease can be accurately modeled outside the body thus increasing the speed and efficiency of discovery. In addition, big data science approaches including next generation gene sequencing and proteomics can be applied to diabetes to better understand disease pathogenesis. Finally, precision medicine research focused on specific features of individual patients is another tremendously exciting direction that could be applied to new diagnostic, disease monitoring, and therapeutic approaches.