The role of PRAS40 in mTOR signaling and insulin resistance

General Research Subject: Type 2 Diabetes

Focus: Insulin Action\Insulin Resistance, Insulin Action\Signal Transduction, Adipocytes

Type of Grant: Career Development

Project Start Date: July 1, 2007

Project End Date: June 30, 2012

Research Description

Insulin resistance is a common pathological state of several human diseases, including diabetes, obesity, hypertension, and cardiovascular disease, that leads to abnormal glucose and lipid metabolism as a result of an impaired metabolic response to insulin. The exact mechanism underlying the development of insulin resistance remains unclear and appropriate therapy for the disease state is not available. A main reason for the lack of knowledge is the complexity of the mechanism that leads to the development of the disease state. What is primarily required to cure the disease state might be to identify missing components involved in insulin resistance development. Recent advances in dissection of signaling pathways have led to insights into how mTOR signaling plays crucial roles in the development of insulin resistance. In many cell types, including liver, adipose, and muscle cells, mTOR activation shuts down insulin receptor functions and makes cells insensitive to insulin. This proposal is intended to elucidate the molecular mechanisms through which mTOR regulates insulin receptor functions by identifying novel mTOR regulators. Identified mTOR regulators will be essential for the treatment of insulin resistance because without the knowledge a complete picture of the regulatory points crucial for the insulin resistance development will never be obtained. Towards the end of this proposal, newly identified components and their functional understanding will provide crucial regulatory points that can be targeted for artificial manipulation of the pathway. The improved understanding in the cause of insulin resistance may help physicians design new therapeutic strategies to fight the disease state.

Reseacher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? This project covers an area of research on the molecular mechanisms underlying the pathogenesis of insulin resistance, a common pathological state of several human diseases, including diabetes, obesity, hypertension, and cardiovascular disease. The exact mechanism underlying the development of insulin resistance remains unclear and an appropriate therapy to prevent the disease state is not available. What is primarily required to prevent or cure the disease state may be to identify missing components involved in insulin resistance development. Recent advances in understanding of cellular signaling pathways have led to insights into how mTOR signaling plays crucial roles in the development of insulin resistance. In many cell types, including liver, adipose, and muscle cells, mTOR activation shuts down insulin receptor functions and makes cells insensitive to insulin. This project aims to elucidate the molecular mechanisms through which mTOR regulates insulin receptor functions by identifying novel mTOR regulators. Our research will be focused on determining functions of PRAS40, a new regulator of mTOR that was recently identified by my group, in the regulation of insulin resistance development. Identified mTOR regulators will be essential for the treatment of insulin resistance because without the knowledge a complete picture of the regulatory points crucial for the insulin resistance development will never be obtained. Although the results might be too basic for clinical applicability, the improved understanding about the cause of insulin resistance may help physicians design new therapeutic strategies to fight the disease state.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? Insulin resistance is a pathological state associated with diabetes that causes abnormal glucose and lipid metabolism as a result of an impaired metabolic response to insulin. My research will be focused on understanding functions mediated by mTOR, an emerging target for the prevention of insulin resistance and a central component of a cellular signaling network that regulates growth and nutrient metabolism. To obtain better understanding of mTOR roles in the regulation of insulin sensitivity in tissues, my proposed research will identify novel molecular components involved in the regulation of mTOR and elucidate their roles in the regulation of insulin resistance development. Recently, my lab made a seminal discovery identifying an mTOR-regulatory protein PRAS40 that plays an important role in the regulation of insulin receptor substrate-1, a protein whose stability is crucial for insulin sensitivity in many tissues. My research will be devoted to characterization of functions of this protein as well as other identified proteins that regulate mTOR and insulin receptor functions. Understanding functions of molecular components in cellular signaling involved in the regulation of insulin receptor functions will be essential to treat insulin resistance because without the knowledge we will never obtain a complete picture of the regulatory points crucial for the insulin resistance development. Towards the end of this project, I believe that newly identified components and their functional understanding will provide new regulatory points for which we can develop a means for artificial manipulation of the pathway activity and eventually help fight the disease state.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? My research has been devoted to understanding the mechanism underlying the regulation of mTOR, an emerging target to prevent insulin resistance, but it was not until 2004 when I started my independent research that I found interests in diabetes research. My lab is in a research environment where I can meet many inspiring scientists who have helped me to find interests in diabetic research topics, which include lipid, glucose metabolism, adipogenesis, and diabetic alteration of nutrient metabolism. Learning more about diabetes and its associated disease states, I recognized the importance of the study on insulin resistance, a serious medical problem affecting near 100 million Americans, and I determined to build my research program in the diabetic study field. Knowing the significant importance of mTOR in the regulation of insulin-mediated metabolism in many tissues, I envision that my proposed research will have a significant impact on the study of the pathogenesis of diabetes. This award will allow me to ensure initiate and continue research projects that have been valid to work or conducted successfully. The research funding from the award program will help develop innovative methods with long-term potential to bring new and important discoveries to the study of diabetes. The award will also help my lab to actively recruit outstanding graduate students and postdoctoral fellows and educate them in the field of cell signaling pertaining to diabetes.

In what direction do you see the future of diabetes research going? Given accumulated knowledge on diabetes, we will identify important roles of many genetic and environmental factors and the interaction between both factors in determining the diabetic states. I envision that more genetic factors will be identified as determinants of diabetes in the future research. This identification will benefit from the recent progress in the genomic research that helps search for new genetic factors. We will learn more about genetic alterations associated with diabetes or the genetic basis of the onset of diabetes. In addition to this study determining genetic factors, we will also need to emphasize studies on identifying the mechanisms through which environmental factors, such as dietary foods, exercise, psychological states, drug, lifestyle, or stress, influence the diabetic states. Once we obtain better knowledge on the complex relationship between the genetic and the environmental factors in the determination of the diabetic states, we will be able to identify more effective target molecules for the treatment of diabetes or therapeutic approaches to prevent the disease.