Antifibrotic Effects of Macropinocytosis Inhibition in Idiopathic Pulmonary Fibrosis
Abstract
Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease of unknown cause. This enigmatic disorder affects approximately 500 per 100,000 adults over age 65 in the United States and is unfortunately increasing in prevalence, leading to rising rates of hospital admissions and deaths. The prognosis is poor, with a significant decline in quality of life and a median survival of only 3-5 years. Although two therapies have been Food and Drug Administration (FDA)-approved, at best they slow the rate of disease progression. Thus, there is an unmet need for a better understanding the pathobiology of IPF to develop more effective therapeutics against IPF. During the progression of pulmonary fibrosis, activated fibroblasts are known to be responsible for excessive extracellular matrix production, increased invasiveness, and resistance to cell death, which ultimately leads to aberrant wound healing, lung thickening, and fibrosis. Thus, it is important to determine the molecular mechanisms that drive profibrotic responses in lung fibroblasts. Macropinocytosis is the process that mediates non-selective engulfment of extracellular fluid with the components contained therein such as proteins and lipids. Macropinocytosis is exploited by various cancer cells to fulfill their nutritional needs in order to grow and metastasize. We are convinced that activated fibroblasts are also utilizing macropinocytosis to promote pulmonary fibrosis. This project will determine whether macropinocytosis inhibition attenuates pulmonary fibrosis using both pharmacological and genetic approaches. Hypothesis: We hypothesize that increased macropinocytosis contributes to the development of lung fibrosis and fibroblast activation. Thus, its inhibition exerts anti-fibrotic effects in animal model of lung fibrosis by reducing profibrotic responses in activated fibroblasts. We also hypothesize that vacuolar protein sorting 34 (Vps34) is essential for macropinocytosis, which in turn confers to fibroblast activation. Specific Aims: Aim 1: To demonstrate that macropinocytosis inhibition attenuates lung fibrosis in mice by inhibiting fibroblast activation. Aim 2: To demonstrate that Vps34 is a key protein in macropinosome formation and contributes to profibrotic responses of lung fibroblasts. Short-Term and Long-Term Impact: The short-term impact of this proposal is to determine the feasibility of using macropinocytosis inhibitors as potential therapeutics to treat IPF using preclinical models of pulmonary fibrosis. The long-term impact of this proposal is to set up a scientifically justified platform to initiate a clinical trial(s) related to repurposing of FDA-approved drugs as macropinocytosis inhibitors to treat pulmonary fibrosis. Long-term impact would be significant if the macropinocytosis inhibitors show therapeutic effects in pulmonary fibrosis, resulting in decreased mortality and morbidity for this deadly disorder. This would impact not only to civilians but also to military personnel and Veterans with pulmonary fibrosis. Relevance to Topic Area: This proposal specifically addresses the Topic Area of Encouragement of Pulmonary Fibrosis and focuses on the development of a novel therapeutic strategy to halt and reverse the progression of pulmonary fibrosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210147
Entities
People
- Konstantin Tsoyi
Organizations
- Baylor College of Medicine
- United States Army