The prevalence of type 1 diabetes (T1D) is on the rise, posing a significant burden on healthcare systems. T1D results from the immune system mistakenly attacking insulin–producing pancreatic β–cells, necessitating lifelong insulin treatment and continuous monitoring of blood sugar levels. The complex inflammatory nature of T1D, coupled with substantial gaps in our understanding of the molecular drivers behind β–cell destruction, presents challenges in developing effective treatment strategies.
The primary challenge this project tackles is the need for more effective approaches to treat T1D by addressing the underlying cause–the destruction of pancreatic β–cells. This requires a thorough understanding of the molecular mechanisms responsible for β–cell damage. This project centers around the role of the Hippo signalling pathway, known for its involvement in regulating organ size and tissue hemostasis. We were the first to demonstrate the pivotal role of the Hippo signaling pathway in β–cell apoptosis, regeneration, and function. Pilot data indicate that the terminal effector of the Hippo pathway, Yes–Associated Protein (YAP), typically repressed in mature β–cells, is upregulated in both exocrine and endocrine compartments of individuals with T1D, acting as a potential regulator of β–cell apoptosis and islet inflammation. Therefore, elevated expression of YAP is a novel metabolic aspect of T1D. We hypothesize that elucidating the molecular mechanisms linked to YAP–induced damage is crucial for the development of targeted therapies for T1D.
The project’s primary objectives are to unravel the role of YAP and its molecular partners in T1D. These objectives include: (1) Identifying how YAP expression is activated in T1D and characterizing the cell types responsible for YAP upregulation. (2) Investigating the expression and cellular localization of YAP partners. (3) Determining single–nucleus RNA–seq (snRNA–seq), single–nucleus multiome (gene expression + chromatin accessibility from the same nucleus), and spatial transcriptome profiling of YAP–expressing pancreatic cells in T1D to identify and characterize cell states, gene regulatory programs, and signaling pathways that define their molecular identity and spatial niche. Utilizing the nPOD collection of healthy and diseased human pancreatic tissue, the project aims to unravel the molecular aspects of islet autoimmunity and β–cell destruction in T1D. This knowledge will serve as the foundation for new therapeutic strategies targeting the Hippo pathway to protect β–cells in T1D.
The work at the Wellcome Sanger Institute will be undertaken under NHS REC Approval19/YH/0441‘Sanger HumanCell Atlasing Project. Defining human cells in terms of gene expression, physiological states,developmental trajectories, and location’ also known as the Human Cell Atlasinginitiative. The data generated from it will contributeto the initiative based on the aim to define all human cell types in terms of their distinctive patterns of gene expression, physiological states, developmental trajectories, and location. This will pave the way to create a reference map of all human cells as a basis for understanding human health and diagnosing, monitoring, and treating disease.
