Using computer science-based approaches to create individualized treatment plans
City of Hope researchers are developing a high-tech analytic tool that promises to revolutionize the way diabetes is treated. The treatment platform uses the combination of both data-driven and expert-based algorithms to generate validated individualized treatment plans. Advanced Diabetes Algorithm Management System, or ADAMS, starts by gathering information on the patient’s health, treatment preferences and other epidemiological and cultural factors. The data is processed using the model-fitting software that gives the physicians not only a basic “overview” of how a patient’s body is metabolizing glucose, but also the results of in silico simulations showing a specific intervention’s likely impact on a patient’s metabolic footprint. Thus, the patient is armed with a comprehensive treatment plan and continued feedback on diet, exercise and medication.
Fouad R. Kandeel, M.D., Ph.D., who is leading this project, believes the program can vastly improve long-time clinical outcomes for large populations of diabetic patients across the globe. Kandeel is directly collaborating with Andrei Rodin, Ph.D., a leader in the field of developing systems biology data analysis methodology, who is working on adapting his secondary data analysis tools to clinical data.
Identifying mechanisms and drug targets for diabetic complications
Diabetes is the leading cause of kidney failure and a significant risk factor for the development of vascular complications like atherosclerosis. Rama Natarajan , Ph.D., is studying mechanisms of atherosclerosis and kidney disease in diabetes. She is using cell, animal and human models to demonstrate how diabetes leads to increased inflammation in blood and kidney cells and is devising approaches to interfere with the production of these inflammatory molecules to slow down diabetic vascular complications
Her team has also studied a gene-control mechanism called RNA silencing, which may play a key role in diabetic kidney disease. In it, cells employ pieces of genetic material called microRNA, or miRNA, to turn genes off. The researchers have identified a key miRNA that creates an overproduction of collagen, which causes damage that can lead to kidney disease and renal dysfunction. By controlling key miRNAs in the kidney, the researchers seek to slow down the cells’ overproduction of collagen and similar proteins and potentially control diabetic kidney disease. They are also similarly examining miRNAs and related molecules that promote inflammation in blood cells and blood vessels under diabetic conditions and approaches to interfere with their actions to control cardiovascular complications of diabetes.
Targeting a key to metabolic syndrome
Sanjay Awasthi , M.D., is studying the role of glutathione metabolism in the development of cancer and type 2 diabetes. He silenced the gene that expresses the protein RLIP76, increasing resistance to the development of chemically induced cancers in animal models. Furthermore, the models showed reduced blood sugar, cholesterol and triglycerides despite a high-fat diet. These findings are expected to lead to the development of novel drugs that targets RLIP76 in order to treat obesity, metabolic syndrome and cancer.
Generating insulin-producing cells from stem cells
One of the major roadblocks to translating stem cell research from the lab to the clinic is the low yield of insulin-producing cells from stem cells. Arthur Riggs, Ph.D., is collaborating with Hsun Teresa Ku , Ph.D., on ways to generate insulin-producing cells from stem cells.
The team is creating new technologies to accomplish this, including synthetic extracellular matrices, structures found in the connective tissues of animals, and genetically reprogram them to adopt a new identity and function.
Creating a drug to mimic the benefits of exercise
In order to develop treatments that slow or prevent the development of type 2 diabetes, researchers must understand the ways in which various insulin responsive tissues respond to fluctuations in diet and energy demand. The laboratory of Janice Huss, Ph.D., investigates mechanisms governing mitochondrial energy metabolism and growth of skeletal muscle in healthy and diseased states. The capacity of skeletal muscle to regulate whole body energy balance, glucose and lipid utilization and to prevent the development of obesity and insulin resistance is determined by its oxidative capacity and it overall mass. Her group has discovered that the Estrogen-related Receptors (ERRs) control interrelated programs of muscle energy metabolism and growth. ERRs control levels of proteins needed for energy metabolism and muscle contraction. These factors are essential for directing metabolic enhancements caused by endurance exercise. Her laboratory is investigating whether targeting ERR genetically and novel drugs could prevent diet-induced obesity or mimic the beneficial effects of exercise on whole body glucose control.
Suppressing a patient’s immune imbalance
Chih-Pin Liu, Ph.D., is developing a new method to correct immune imbalance that may cause diabetes by taking a patient’s own regulatory T cells, which help to maintain balance in the immune system, and expanding them in the laboratory, then re-administering the cells to the diabetic patient. Liu’s promising research has already shown that Treg cells fortified in this way are as potent as normal Treg cells in suppressing the pathogenic immune imbalance that leads to a patient’s inability to produce insulin.
From nature, a potential treatment for diabetes
The lab of Wendong Huang , Ph.D., recently discovered that a chemical derivative of the barberry plant, berberine, may block diabetes by activating a receptor that increases the body’s sensitivity to insulin and helps maintain glucose balance. Berberine, which is approved by the Food and Drug Administration to treat other conditions, could be tested in humans for its potential effect on diabetes. Huang is also interested in small RNAs known as microRNAs (miRNAs), which have emerged as key regulators of genes related to metabolism and diabetes. He discovered a specific miRNA that, when overproduced in animal models, improves insulin sensitivity and prevents obesity-related metabolic complications. That miRNA is now a potential target for type 2 diabetes therapies.
Real-time imaging of islet cells after transplant
Fouad Kandeel, M.D., Ph.D., is also developing methods to directly monitor islet survival and function after transplantation into the liver using a radio-labeled protein developed at City of Hope that binds to human islet cells, an approach that has been successful in mouse models. Real-time imaging of the transplanted islet graft will provide critical information about cell health and dysfunction and help to ensure graft survival. It could also be used to monitor native islet cells in patients newly diagnosed with type 1 diabetes. This leading-edge technology will allow physicians to assess the success of islet cell translation with more accuracy and timeliness than traditional assessment methods.
Developing a curative therapy for overt type 1 diabetes
Autoimmune type 1 diabetes is caused by autoimmune destruction of insulin-producing cells. Cure of overt type 1 diabetes requires the simultaneous stoppage of autoimmunity and regeneration of insulin-producing cells. At this time, the only therapy with the potential to do this is the combination of induction of mixed chimerism and administration of growth factors that has been recently developed by the laboratory of Defu Zeng , M.D. Mixed chimerism is the co-existence of donor and recipient hematopoiesis and immune system that can cure autoimmunity. Once autoimmunity is stopped, injection of growth factors can augment the regeneration of insulin-producing cells and subsequently cure the disease.
Mixed chimerism can be established by hematopoietic cell transplantation (HCT), but the classical HCT procedure requiring total body irradiation or high-dose chemotherapy has strong toxicity and the potential to cause graft versus host disease (GvHD). Zeng’s lab has found that anti-CD3 monoclonal antibodies can replace total body irradiation or high dose chemotherapy for induction of mixed chimerism. This new procedure is non-toxic and avoids the side effect of GvHD. Now, in collaboration with Arthur Riggs , Ph.D., the department chairman, Zeng’s lab is working on translating this novel therapy into clinical application by making antibodies that can be used in patients and by conducting experiments with large animal models.
Exploring the epigenetic and genetic underpinnings of obesity and diabetic complications
Rama Natarajan, Ph.D., is leading examinations into the role of epigenetics in diabetes and its complications, as well as genetic variations that make some people more susceptible to obesity and metabolic disease. Susceptibility to both obesity and diabetes depends on genetics and environmental factors (like high calorie and high fat diets) that affect our epigenes or epigenetics. Epigenetics refers to changes that are made to our genes and can be passed on to future generations — but are not written into our DNA. Dr. Natarajan’s laboratory is using state-of-the-art epigenome profiling to decipher epigenetic changes that promote inflammation and metabolic memory in diabetes, and also predispose to diabetic vascular and kidney disease in animal and human subjects. Because epigenetic changes are reversible, this research could lead to the development of epigenetic drugs to treat diabetes and its debilitating complications.
Furthermore, in collaboration with other researchers, Natarajan is using novel animal models to map specific genome regions that become active when the subjects consume a diet high in fat and sugar. The goal is to discover unique genes and develop therapies to turn them on or off to give a patient the same genetic protection that some members of the general population have against obesity, regardless of diet.