Evaluation of Human Adipose Tissue Stromal Heterogeneity in Metabolic Disease Using Single-Cell RNA-seq
Abstract
This proposal directly addresses the Peer Review Medical Research Program Topic Area of Metabolic Disease. The obesity epidemic has enormous and widespread implications for America at large, but especially for the US Military and Veterans. Nearly three-quarters of Veterans are overweight and a quarter have a diagnosis of diabetes for which obesity is the primary risk factor, resulting in five billion dollars of added cost for the military and Veterans medical care systems. In this project, we propose to study in detail how cells within fat tissue interact to cause obesity and its related complications. Fat tissue is an incredibly complex tissue made up of cells that store excess calories in the form of lipids (the fat cells) along with many types of immune cells, fat cell precursors, and support cells. During development of obesity, these cells act in concert to remodel the fat tissue, allowing for the tissue expansion characteristic of weight gain. During the process of this remodeling, fat cells have been shown to become stressed and dysfunctional, leading to tissue inflammation and further recruitment of many different kinds of inflammatory immune cells into the fat tissue. It is not even known what are all the types of cells that live in the fat tissue, much less how each type is involved in the process of the fat tissue becoming dysfunctional. In the past, trying to answer these questions has been complicated, laborious, and technically difficult, relying on determining what is happening in all the cells together rather than what is happening in individual cells. As a result, our understanding is incomplete. We propose to use a cutting-edge research technology called single-cell RNA-seq that can identify a signature for each cell type and classify individual cells into cell types. The main innovation is the examination of thousands of individual cells from a complex tissue rather than averaging their response, thereby maintaining an ability to determine how each of these individual cells contributes to the output of the whole tissue. We will use this technique to assess the cell type content of fat tissue from human subjects with a spectrum of metabolic health to determine how the cell type content within fat tissue changes during development of metabolic disease. From these data, we can determine which cell types are associated with disease and furthermore we can assess what is changing in those cells to cause the fat tissue dysfunction. These results will allow us to identify novel molecular targets against which we can design medicines to combat obesity and its related complications.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510251
Entities
People
- Linus Tsai
Organizations
- Beth Israel Deaconess Medical Center
- United States Army