A Novel 3D Scleroderma Skin Model to Test Therapeutic TRPC6 Modulation
Abstract
Scleroderma is a rare disease commonly characterized by chronic hardening (fibrosis) of body tissues, including the skin, due to excessive accumulation of collagen. Despite intensive research, no therapies are effective in treating scleroderma-related skin disease. To test the value of new treatments, human three-dimensional (3D) skin models offer significant advantages over animal models. However, existing 3D skin models are limited in value due to their inability to assess the production of collagen, a critical component of scleroderma. Thus, there is an urgent need for the development of more efficient and reproducible human 3D skin models as a means for the screening of novel scleroderma treatments. Therefore, the main goal of the first project part is to develop, characterize, and validate a novel 3D human fibrotic skin model (scleroderma model) that allows determining the overproduction of collagen and its normalization following exposure to treatment. We will use a cutting-edge technology called electrospinning to create tissue analogs with high similarity to scleroderma skin. Our preliminary results show that activation of TRPC6 (an ion channel present in the skin) leads to increased collagen synthesis and crosslinking, which in turn can be prevented by pharmacological inhibitors of TRPC6. This highlights that TRPC6 constitutes a promising anti-fibrotic drug target for the targeted treatment of scleroderma-related skin problems. Therefore, the main goal of the second project part is to investigate the potential of TRPC6 as a therapeutic target of scleroderma. Experiments will first be conducted in classical 2D culture, thereafter in the new 3D human fibrosis model, and subsequently in a well-established mouse model. We will also utilize these experiments to verify the potential of using the new electrospun 3D fibrotic skin model to reduce costs, improve scientific rigor, and speed up the discovery of scleroderma therapeutics. The proposed project is relevant to the FY21 Scleroderma Research Program Idea Development Award Focus Areas because it will (1) develop a novel 3D fibrotic skin model (scleroderma model) that can be used for preclinical screening approaches in drug testing and development and (2) evaluate the potential of TRPC6 as a new therapeutic target using the new fibrotic skin model. We believe that the project will help scleroderma patients that suffer from hardening and tightening of the skin and associated problems, such as limited range of motion of the hands and extremities, tightness of the face, and change in body habitus. The development of a novel, fibrotic 3D skin model for scleroderma in the first part of the project will promote the development of new therapeutic approaches (Innovation 1). The second part of the project will directly investigate a new therapeutic approach with high potential and will hopefully result in the first effective treatment for scleroderma patients suffering from skin hardening and tightening (Innovation 2). Although further experiments on safety and efficacy will be needed following a positive study outcome, this research will lay the groundwork to better understand the molecular mechanisms underlying the development and progression of scleroderma and to realize improvements in the care and quality of life of those affected by scleroderma-induced skin alterations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210735
Entities
People
- Karin Wuertz-kozak
Organizations
- Rochester Institute of Technology
- United States Army