Innovative Therapy and Underlying Mechanism of Neuraminidase-1-Driven Pulmonary Fibrosis
Abstract
FY20 PRMRP Topic Areas addressed by the proposed research project: Pulmonary Fibrosis. The human body naturally heals injuries by forming scars, either in the skin or in the internal organs. In some individuals, the scarring process gets out of control, resulting in massive accumulation of the scar tissue. When such exaggerated scarring develops in the lung, it is called “pulmonary fibrosis.” The excessive scar deposits in the lungs interfere with the patient’s ability to absorb oxygen from the air, making pulmonary fibrosis a dangerous condition. Its severity is particularly pronounced in patients with so-called idiopathic pulmonary fibrosis. Pulmonary fibrosis also complicates a number of other diseases and can develop as a result of exposures to harmful environments, such as those occurring in the military. Being a male and smoking also predispose to pulmonary fibrosis, increasing the relevance to military Service members. Women also develop pulmonary fibrosis. African-American patients often have pulmonary fibrosis in its more severe form. The continuously increasing roles of women and African Americans in the military further elevate the relevance to military Service members. Pulmonary fibrosis becomes more prevalent and severe with age, making it relevant to the healthcare needs of Veterans. Despite the biomedical and socioeconomic importance posed by pulmonary fibrosis, the therapeutic options for these patients are limited, and better therapies need to be urgently developed. Scientists including us are investigating the underlying disturbances in body molecules that are involved in pulmonary fibrosis in order to develop better therapies based on such understanding of the disease process. We recently identified an enzyme, neuraminidase 1, as a key player in fibrosis. This is a highly innovative project, considering the rather limited current knowledge about the role of neuraminidase 1 in fibrosis. Our data indicate that neuraminidase 1-selective pharmacological inhibition in vivo utilizing novel small molecule compounds may be therapeutic. We will capitalize on this finding in Specific Aim 1 to preclinically develop a novel, neuraminidase 1-targeting, antifibrotic therapy. We will also explore a novel molecular mechanism mediating the profibrotic action of elevated neuraminidase 1, to which we have been led by a combination of pre-existing knowledge in the field and our own findings. We found that a molecule called soluble mucin 1 ectodomain, which has been used as a biomarker for fibrotic disorders, is released by neuraminidase 1. Specific Aim 2 will explore whether soluble mucin 1 ectodomain mediates the profibrotic effect of neuraminidase 1. This is a highly innovative, original project that develops a new therapy for, as well as explores a new mechanism of, a severe disease, pulmonary fibrosis, which particularly affects military Service members, Veterans, and patients in the general population. A successful completion of this work will improve the quality of life, care for, and survival of patients in these populations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110041
Entities
People
- Irina Luzina
Organizations
- United States Army