Kim, Do-Hyung , PhD
SH3BP4 as a novel negative regulator of mTORC1 signaling and insulin resistance
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Signal Transduction, Integrated Physiology, Integrated Physiology\Amino Acid Metabolism
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Insulin resistance is a common pathological state of many human diseases, including diabetes, obesity, hypertension, and cardiovascular disease, and of aged people, which is associated with 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 an appropriate therapy is not available. A main reason for the lack of knowledge is the complexity of the mechanism that leads to the disease state. What is primarily required to cure the disease state is to comprehensively understand the molecular processes involved in insulin resistance.
Recent studies using genetic/biochemical tools and inhibitors revealed an increasing role of mammalian target of rapamycin complex 1 (mTORC1) in insulin resistance development. Sustained activation of mTORC1 inhibits insulin signaling to Akt and insulin-stimulated glucose transport in many cell types including adipocytes and skeletal muscle cells and increases insulin resistance in fat tissue. This proposed research will introduce a novel component SH3BP4 in the pathway and provide a detailed mechanism of how SH3BP4 regulates mTORC1 signaling in response to amino acids and insulin. This contribution will transform our understanding of amino acid- and insulin-regulated mTORC1 signaling to an unprecedented level of detail. Furthermore, the detailed understanding of the component will enable development of novel strategies that specifically manipulate amino acid- and insulin-regulated-mTORC1 signaling. The new pathway is expected to introduce a more efficacious approach to alleviate mTORC1-associated metabolic disorders with overcoming problems that have been associated with rapamycin or its analogs.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This basic research project investigates the roles of a previously-unknown factor involved in the regulation of nutrient sensing and mTORC1 (mammalian target of rapamycin complex 1) signaling and insulin resistance development. The protein named SH3BP4 (SH3 binding protein 4) has been identified by my group as a novel binding protein of Rag GTPases that play crucial roles in amino acid-sensing mTORC1 signaling. Dys-regulation of mTORC1 signaling or hyperactivation of mTORC1 is closely linked to the development of insulin resistance. In many cell types, including liver, adipose, and muscle cells, mTOR activation suppresses insulin receptor functions and makes cells insensitive to insulin.
Our preliminary study revealed that SH3BP4 is an important component as a negative regulator for cellular responses to amino acids, insulin and glucose and required for appropriate regulation of cell growth and metabolism. Furthermore, SH3BP4 is a substrate of AKT thus it appears to play a critical role in coordinating amino acid and insulin signaling pathways. If we understand better how the negative function of SH3BP4 is regulated and disturbed in diabetes, it will significantly advance our knowledge on cellular responses to nutrients and on the molecular basis for insulin resistance development. The detailed understanding of the components and interactions involved in the regulation is expected to enable development of novel strategies that specifically manipulate amino acid- and insulin-regulated mTORC1 signaling. Once such strategies become available, there is the promise that better therapeutic approaches for mTORC1-related diseases such as diabetes, obesity, skeletal muscle atrophy and aging-related diseases could be developed.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Although researchers have been investigating the cause and cure for insulin resistance for many years, our understanding of the disease state remains not comprehensively understood mainly due to the complex nature of the regulatory interaction and metabolism in cells and our body. The mTORC1 pathway is one of the key pathways that researchers have identified to be important for the development of insulin resistance. The function of this pathway is to sense cellular nutritional (amino acid, glucose and insulin) status and coordinate cellular growth and metabolism. When this pathway is mal-functioning, cells would grow or metabolize abnormally.
Dys-regulation of mTORC1 signaling or hyperactivation of mTORC1 is closely linked to the development of insulin resistance. In many cell types, including liver, adipose, and muscle cells, mTOR activation suppresses insulin receptor functions and makes cells insensitive to insulin. The mTORC1 pathway is regulated by many factors including amino acids, glucose, insulin, IGF1, growth factors, several oncogenes and tumor suppressors, and cellular stress. If we understand clearly how dys-regulation of mTORC1 signaling occurs in diabetes, we will have a better idea to prevent the dys-regulation. Since hyperactivation of mTORC1 has been shown to be one of the major contributions to insulin resistance, an approach to reduce the hyperactivation could be a potential way to suppress insulin resistance.
Our study will improve the fundamental knowledge on mTORC1 signaling by elucidating the functions and regulations of a newly-identified negative regulator of mTORC1. Our study on the negative regulator of mTORC1 will provide novel insight into the development of anti-diabetic targets and transform the current therapeutic stratgies for diabetes. The elucidated new pathway is expected to introduce a more efficacious approach to alleviate mTORC1-associated metabolic disorderes with overcoming problems that have been associated with rapamycin or its analogs.
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 on diabetes is important for me in two parts. First, diabetes research is tightly linked to my scientific interests. The overall interest of my research is to understand the biological networks that coordinately regulate metabolism and growth. It is becoming clear that diabetes needs to be understood in the context of molecular networks rather than in a single molecular context. Studying diabetes has provided many opportunities to me to learn about molecular metabolism and how it is linked to cellular signal transduction and how their disturbance can cause metabolic problems in cells. Second, diabetes research is important for me because I have a strong motivation and belief that our basic research may make an important contribution to our understanding of diabetes and development of the cure.
My proposed research will have a significant impact on the study of the pathogenesis of diabetes. It is important for me as a biologist to believe that discoveries we make will ultimately contribute to improvement of human health. Newly-discovered genes and factors, such as SH3BP4 that we propose in our study, are fundamental to the development of new drugs. This is a strong driving force for my group to conduct the basic research to identify novel factors involved in diabetes.
My laboratory research has been supported by the ADA and the NIDDK for several years. In paritcular, the Career Development Award from the ADA has played a very important role for my research group in establishing research projects on diabetes and discovering several important factors. This basic research award will allow my group to continue on the research projects that have been developed with funds from the ADA and NIDDK. The research funding will enable us to develop innovative methods and ideas with a long-term potential to bring new and important discoveries to the study of diabetes. The award will also enable my group to recruit promising graduate students and scholars and train them in diabetes research field.
In what direction do you see the future of diabetes research going?
One of the most distinctive changes that has been occurring in recent years is the increase of young populations with diabetes and obesity. What genetic and environmental factors contribute to this change is important, and many of future researches may intend to identify these factors. Recent studies have led us to understand individual difference between patients in the causes, symptoms and drug efficacies, and epigenetic changes and regulation in metabolism has become more clear. More examples of epigenetic regulation by small metabolites may be identified. More studies may be oriented to such a direction.
Recent GWAS studies have revealed many previously unseen links of diabetes to new genes. This type of global genomic analysis may provide new insight into the genetic factors and may be important to understand individual difference. In relation to this, the systems approaches to analyze the gigantic data sets from genomic studies may continue to be of high demand. Such systems studies may include genomics, proteomics and metabolomics approaches. Novel regulatory factors, such as small regulatory RNAs and small metabolites, may be identified and characterized in their functions in diabetes and insulin resistance. More integrative tools may become important for the future to understand the interactions between the identified factors, genes and environments. In addition, many more researches may be oriented to environmental factors, such as dietary foods, exercise, psychological states, drug, lifestyle, or stress, and understanding the molecular basis of the contribution of those factors to diabetes. Since drug development highly relies on clear understanding of the drug effects on cellular physiology, better elucidation of celular molecular networks may continue to be important for future drug development.
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