CRISPR-Based Gene Editing to Induce Thermogenic Adipose Tissue in Type 2 Diabetes
Abstract
This project addresses the severe problem of type 2 diabetes (T2DM) in our general population and in our Veterans. T2DM is the most common form of diabetes, affecting a remarkable 1 in 10 adults in the USA. It is a chronic disease that causes many damaging complications, including blindness, amputations, kidney disease, and heart disease. Its toll on our healthcare system is also tremendous. In 2012, the USA spent $244 billion for treatment of T2DM and its complications or $322 billion when loss of productivity due to inability to work is included. That amounts to $1,000 a year for each American. The most alarming aspect of this statistic is that it is 48% higher than it was in 2007. One would think that curing T2DM would be a simple matter of losing excess weight, for example with diet and exercise, since T2DM is related to weight gain. But this is not true. Many individuals develop T2DM with only little weight gain, and losing those few extra pounds is almost impossible, especially as we get older. In India, an even larger percentage of the population has T2DM, despite the fact that most people are thin by our standards. We believe that the real cause of diabetes is not excessive adipose tissue, but the development of unhealthy forms of adipose tissue. Our proposal seeks to turn “unhealthy” adipose tissue into its “healthy” form that burns rather than stores fats, using very new methods that can change human gene expression in a safe manner. Adipose tissue has many different and important functions. For example, fat is in our heels, providing important mechanical support for walking and running. Fat is also near our intestines, providing protection from microorganisms in our digestive system. The form of fat that is under our skin (“white”) is useful for storing extra energy to use during fasting or exercise. But there is also a form of fat called “beige” fat that keeps our heart and blood vessels warm, and also produces hormones that keep our metabolism healthy. Importantly, “beige” fat cannot be found in people with T2DM, suggesting that the absence of “beige” adipocytes (the fat cells that make up fat) may be causing the disease. Importantly, “beige” adipocytes express genes that increase metabolism, burn fat and produce healthy hormones, while “white” adipocytes do not. We have discovered a gene (denoted RIP140) that, when disrupted or deleted, can convert “white” adipocytes into “beige” adipocytes, and we believe that turning off this gene by the methods we have developed will lead to a powerful therapeutic strategy for effectively treating T2DM. In the past couple of years, a new technique for turning genes off has been discovered. This technique uses an enzyme (Cas9) and a molecule called sgRNA to turn off specific genes. We have developed a way to send Cas9 and sgRNA into mouse and human cells, by packaging them into small vehicles called CriPs, which then can enter human cells. CriPs represent the technology we will further develop in this project to test whether they will effectively delete the RIP140 gene, convert white fat to “beige” fat and alleviate high blood glucose and T2DM. We have a plan by which we can send CriPs to “white” adipocytes and convert them into “beige” adipocytes in the intact mouse. Very importantly, we use human fat cells for our research, and we can study them in living mice by special techniques we developed. Thus, our research is poised to exploit our unique abilities to test the effects of many variations of CriPs on human fat cells in a living organism (“humanized mouse”) to optimize their therapeutic effectiveness and test hypotheses that can lead to therapeutic strategies for T2DM.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810398
Entities
People
- Michael Czech
Organizations
- United States Army
- University of Massachusetts Medical School