RESEARCH OVERVIEW
Intense research efforts have been taken to better understand how signalling effectors, such as receptors, kinases, transcription factors, and transport proteins, contribute to metabolism and the development of metabolic diseases, including obesity and diabetes. However, one area of research that is routinely overlooked is how these factors are accurately coordinated within a cell. Changes in the accuracy or duration of signaling events may have detrimental consequences and lead to the development of metabolic diseases and, in some cases, cancer.
Each signalling effector belongs to one or more pathways, and they often participate in signalling networks. What often gets overlooked are the factors within a cell that determine where in the cell they are "turned on/off," when they are needed, and how their activities are regulated.
The Lim Lab focuses on scaffold / adaptor proteins belonging to the 14-3-3 protein family. In mammals, 7 members have been identified, and although they were originally discovered int he brain, they can be found in many tissues and cells within the body!
14-3-3 proteins have the ability to interact with multiple effector molecules involved in whole-body metabolism, but whether they directly contribute to metabolic processes is not well understood, nor is it known whether changes in their function can lead to the development of diabetes and obesity.
RESEARCH AREAS
1. 14-3-3 proteins in adipocytes
Building upon our previous finding that one member of the 14-3-3 family, 14-3-3zeta, is essential for adipocyte, or fat cell, development, the Lim Lab is trying to further understand what other processes in fat cells are influenced by 14-3-3zeta.
We also found that increased levels of 14-3-3zeta influences the development of obesity, and we are actively trying to understand how 14-3-3zeta influences this process.
The Lim lab also uses new methods to better understand how 14-3-3zeta controls the development of adipocytes. Taking advantage of unbiased approaches, such as proteomics, RNA-Seq, ChIP-Seq, future studies are aimed at creating a framework of the biological processes influenced by 14-3-3zeta during adipocyte development.
2. 14-3-3 proteins in beta-cells
Some of the well-established roles of 14-3-3zeta, and its related family members, are its ability to promote cell survival and control cell proliferation.
We previously found that 14-3-3zeta controls the survival of an immortalized pancreatic beta-cell line. This was in stark contrast to our use of mice that completely lack 14-3-3zeta, which displayed increased number of pancreatic beta-cells!
The Lim Lab is now exploring what 14-3-3zeta specifically does in pancreatic beta-cells. We are examining how it influences beta-cell survival and function and testing whether we can promote beta-cell expansion by targeting 14-3-3zeta.
3. Harnessing the 14-3-3zeta interactome to identify new regulators of physiological processes
14-3-3 proteins are unique in that they can interact with proteins that contain specific 14-3-3 phosphorylation motifs. To date, at least 1800 proteins have been identified as 14-3-3 protein binding partners. Taking advantage of this observation, the Lim Lab is using proteomic-based approaches to understand how metabolic processes influence the interactome of 14-3-3zeta, and genome-wide screening approaches are being used to target each interacting partner to understand whether they control various aspects of metabolism. Using this approach, we have recently identified new roles of RNA splicing proteins in adipocyte development.
SOURCES OF FUNDING
