Insulin receptor condensates in health and disease

PROJECT SUMMARY/ABSTRACT Insulin resistance is a blunted signaling response that is associated with the development of many diseases, including, type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated fatty liver disease (MAFLD). Insulin resistance and its associated diseases are some of the leading causes of morbidity and death worldwide. Despite extensive knowledge of the drivers and stressors that contribute to insulin resistance, there is a relative lack of consensus for a molecular, mechanistic model that explain how insulin resistance occurs. Recent reports indicate that signaling factors can form dynamic biomolecular condensates, which are mesoscale cellular compartments that concentrate biomolecules and have liquid-like properties. A condensate model provides a new framework to explain how changes in the physico-mechanical features of condensates promote the development of insulin resistance. I discovered that the insulin receptor (IR) forms dynamic, liquid-like condensates that have insulin-dependent functional activity. In insulin resistance, IR condensates become dysfunctional. IR condensate dysfunction is in part due to increased levels of reactive oxygen species (ROS). Furthermore, I found that IR condensate dysfunction is also seen in patients with type 2 diabetes. However, it remains unclear how IR condensates form in heathy cells and become dysfunctional in insulin resistance. I hypothesize that in insulin sensitive cells domains of IR promote condensate formation, which when oxidized in insulin resistance drive IR condensate dysfunction. To address this, I will 1) dissect the molecular requirements for IR condensate formation and 2) determine the molecular changes that promote dysfunctional IR condensates. These aims will advance our understanding of how dysregulated IR condensates promote insulin resistance and will lead to new innovations in the treatment and prevention of insulin resistance and its associated diseases, including type 2 diabetes, obesity, and metabolic dysfunction-associated fatty liver disease. As the PI of this project, I, Dr. Jesse Platt MD PhD, am a physician-scientist performing mentored research in the lab of Dr. Richard Young. My long-term career goal is to develop an independent, academic research laboratory that investigates the role of biomolecular condensates in gastrointestinal health and disease and leverages this knowledge for therapeutic benefit. I will spend 80% of my time engaged in the proposed research, and 20% of my time caring for patients with liver disease. Dr. Young is an expert in biomolecular condensates. I will be guided by an exceptional committee of mentors, including: Dr. Phillip Sharp, Dr. Linda Griffith, and Dr. Rudolf Jaenisch. I will obtain training in biochemistry, microscopy, and mass spectrometry while developing skills in grant writing and leadership. With an outstanding institutional environment, training plan, career development plan, mentorship, and proposed research, this K08 award will enable me to conduct groundbreaking research and transition to independence.