The Hippo Awakens: Re-expression of the Hippo Pathway Effector YAP as a Novel Mechanism in ß-Cell Autoimmunity and Destruction in Type 1 Diabetes

Context: The prevalence of type 1 diabetes (T1D) is increasing, imposing a significant burden on healthcare systems. T1D arises when the immune system mistakenly destroys insulin-producing pancreatic ß-cells, necessitating lifelong insulin treatment and continuous blood sugar monitoring. The complex inflammatory nature of T1D, along with significant gaps in understanding the molecular drivers of ß-cell destruction, presents challenges in developing effective treatments. The challenge addressed: This project tackles the need for more effective T1D treatments by addressing the underlying cause - the destruction of pancreatic ß-cells. Current therapies only alleviate symptoms, underscoring the importance of strategies that prevent or delay ß-cell demise. This requires a thorough understanding of the molecular mechanisms responsible for ß-cell damage. This project centers around the role of Yes-associated protein (YAP) in the Hippo signalling pathway, known for its involvement in regulating organ size and tissue hemostasis. I was the first to show the crucial role of Hippo pathway components, including YAP, in islet/ß-cell biology and their pathophysiology in diabetes. My pilot data indicate that YAP, typically repressed in mature ß-cells, is upregulated in individuals with T1D in both exocrine and endocrine compartments. This upregulation acts as a positive regulator of ß-cell apoptosis and islet inflammation, potentially triggering autoimmunity and ß-cell loss in T1D. Therefore, elevated YAP expression in the pancreas represents a novel metabolic aspect of T1D. Aims and objectives: The primary objectives are to unravel YAP's role in T1D and explore strategies to block its downstream pathway to protect ß-cells. These objectives encompass: (1) Assessing whether YAP antagonism using well-established pharmacological inhibitors of YAP can protect ß-cells from inflammation and destruction in T1D. (2) Determining the molecular mechanisms underlying YAP's regulation and actions in T1D using advanced methodologies such as spatial transcriptomics, high-plex tissue imaging, and loss- and gain-of-function cell-based models. Using multi-model cell systems - including healthy and T1D human pancreatic tissue, disease-relevant in vitro and ex vivo T1D models, and established immune cell-islet interaction cultures, the project aims to outline a critical path for targeting the Hippo/YAP pathway in preclinical and future clinical studies. Potential applications and benefits: Over 4.3 million people in the UK have diabetes, with approximately 8% affected by T1D, which profoundly impacts their quality of life, daily routines, and mental health. Managing T1D incurs substantial costs, including medications, medical equipment, hospital care, and associated healthcare services. The NHS allocates at least £10 billion annually to diabetes, about 10% of its entire budget. This research aims to advance T1D therapy by investigating YAP as a dysregulated factor and an initiator of immune imbalance in T1D. Successful findings could open avenues for signaling-based T1D therapies leveraging the Hippo/YAP pathway. Moreover, a significant fraction of people with type 2 diabetes (T2D) eventually become insulin-dependent due to ß-cell damage, making this research relevant to many millions with diabetes. Existing drugs targeting YAP in oncology trials could be repurposed for rapid assessment in T1D. The direct beneficiaries of this research are individuals with T1D, as it aims to protect ß-cell mass, improve glycemic control, and reduce long-term complications. This would enhance quality of life and reduce the burden on healthcare systems by decreasing costs and resources needed for lifelong insulin therapy and addressing outcomes of poor long-term control (cardiovascular diseases (CVDs), retinopathy, neuropathy, etc.).