Mechanisms of Pulmonary Lesions in TSC LAM
Abstract
Tuberous sclerosis complex (TSC) is a rare genetic disease affecting multiple organs/systems including lung. Lymphangioleiomyomatosis (LAM) is a major clinical manifestation of TSC lung disease, affecting about one-third of women with TSC. Clinically, the progressive pulmonary lesions in LAM can lead to impaired respiratory function, oxygen dependence, and death. However, the related pathogenic mechanisms underlying LAM pulmonary lesions (cysts and nodules) remain unclear, and development of animal models that mimic LAM pathogenic process has been challenging. Using state-of-the-art technology, we have successfully generated a mouse model in which Tsc2 genetic deletion can be induced specifically in lung mesenchymal cells to avoid embryonic death caused by whole body Tsc2 deletion. Our preliminary studies found that the lung-specific Tsc2 mutant mice had abnormal development of alveoli (the delicate air sacs that allow oxygen to move from the air to the blood stream) and lung cysts (enlarged airspaces that resemble the lung cysts occurred in LAM), followed by proliferative nodular formation in adulthood. These resemble to the abnormal changes seen in TSC-LAM patients. Using this new mouse model, the following questions will be addressed in this research project: (1) What are the dynamic processes for the cystic and nodular initiation and progression? (2) How do these abnormal changes occur? (3) Why are there reduced alveolar growth and cyst formation when Tsc2 is deleted in certain subpopulations of lung mesenchymal cells vs. nodular proliferation when Tsc2 is deleted in other subpopulations? (4) What are these subpopulations and their progenitor cells and where are they located? This basic research project will lead to important new knowledge to understand the pathogenesis of TSC-LAM. More importantly, the new and valid mouse model of TSC lung disease will be extremely useful to the field of TSC research, particularly as an important preclinical platform for testing novel therapeutic strategies in future to treat and prevent TSC lung disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710173
Entities
People
- Wei Shi
Organizations
- United States Army