Relaxin for the treatment of diabetes-related fibroinflammation

Diabetes affects 537 million persons worldwide and 30 million in the USA, and is the 8th leading cause of death. The combination of inflammation and fibrosis (fibroinflammation) in multiple organs drives progression of the disease and its complications. There is currently no effective treatment for multiorgan fibroinflammation in T2DM, and therefore this study has high significance to the understanding and treatment of diabetes. The hormone relaxin has anti-fibroinflammatory effects in models of single organ fibrosis, but has not been studied in the context of T2DM. This study will address critical knowledge gaps in the use of new small molecule and long-acting peptide relaxin analogs as a treatment for fibroinflammation in T2DM, and will be the first study to directly test the hypothesis that relaxin receptor activation will reduce multiorgan fibroinflammation in models of T2DM. The study will use novel reporter mice and state-of-the-art in situ hybridization approaches to monitor expression of the relaxin receptor (RXFP1) during T2DM progression. The proposed studies will advance the field toward clinical use of relaxin in T2DM treatment, and therefore will have a potentially high impact. Three Specific Aims are proposed: 1. Determine the efficacy of a long-acting peptide RXFP1 agonist in preclinical models of fibroinflammation in type 2 diabetes. 2. Treatment of diabetes-associated fibroinflammation with an orally-delivered small molecule RXFP1 agonist. 3. Determine the expression of RXFP1 in fibroinflammatory organs in type 2 diabetes. This study will use two mouse models of T2DM, including a genetic (db/db) model and a high fat diet based model. In Aim 1, a novel peptide-based long-acting relaxin receptor agonist will be used to treat diet-induced or genetic T2DM in mice to determine the effects on fibroinflammation in the liver, heart, kidney, and adipose tissue. In Aim 2, we will test a small molecule relaxin receptor agonist in a humanized relaxin receptor mouse to determine the effectiveness on diabetes-associated multiorgan fibroinflammation. We will use a novel reporter mouse strain to monitor the expression of the relaxin receptor RXFP1 in organs with fibroinflammation in the high fat diet model, and by in situ hybridization in the db/db model. Isolated RXFP1-expressing cells will be treated with relaxin to determine the specific signaling pathways activated in each cell type. Key findings will be confirmed using human tissue. These Aims have been designed to answer two fundamental questions: Are small molecule and long-acting RXFP1 agonists as effective or more effective than relaxin in reducing fibroinflammation in T2DM? The second question is, what are the potential relaxin target cells in T2DM? Our studies testing therapeutic efficacy and identifying relaxin target (RXFP1-positive) cells and their associated organs will inform decisions about the timing and targeting of relaxin-based therapies.