Saving the Walking Dead: The delayed effects of radiation and mitigation by blocking the TGFβ‐1 pathway

Abstract

Fibrosis of the lungs in patients who have undergone radiation therapy is a silent killer, inducing dense scar tissue in injured areas. Transforming growth factor beta 1 (TGFβ‐1) plays a role in the development of fibrosis. Radiation fibrosis takes months to develop. Consequently, people who are exposed to radiation to their lungs can die suddenly from pulmonary fibrosis. Latent TGFβ‐1 is stored in the extracellular matrix and is activated by the binding of an AV integrin to the arginine, glycine, and aspartate (RGD) amino acid sequence in the prodomain. Inside of the TGFβ‐1 is a ring‐like structure containing a solvent. Two prodomain arms in the structure connect to form a crossed V‐shape surrounding the growth factor monomers. These arms connect to form a bowtie with disulphide links close to the RGD sequences. The arm domain is composed of two anti‐parallel, four‐stranded beta sheets which contain hydrophobic faces. Active TGFβ‐1 binds to receptors on the surface of cells which signal to other proteins called SMADs, by adding phosphates to the SMADs. This step is inhibited by the medicine currently being tested, IPW‐5371. To understand the long‐term effects of radiation and the structurefunction relationship role of TGFβ‐1, the Divine Savior Holy Angels High School SMART (Students Modeling A Research Topic) Team designed a model of TGFβ‐1 using 3D printing technology. Currently, research is being conducted into fibrosis from activated TGFβ‐1 due to radiation exposure and IPW’s ability to reduce delayed injury to many organs that are exposed to radiation.Support or Funding InformationNIAID award HHSN272201800012C to Innovation Pathways, Palo Alto and NIAID U01AI133594 to the Medical College of Wisconsin.