Interstitial lung disease (ILD) comprises a group of more than 130 disorders characterized by scarring, or fibrosis, of the lungs. The causes of some of the ILDs are known, including those associated with connective tissue diseases such as systemic sclerosis (SSc, or scleroderma). Despite intense study, however, the basic mechanisms responsible for the initiation and perpetuation of fibrosis remain elusive. This proposal outlines a detailed 5-year scientific and career development plan designed to facilitate the applicant's successful transition to the role of independent investigator and provide a solid foundation for her to become a world-class researcher in matrix biology and fibrotic lung disease. Work performed in the mentor's laboratory has demonstrated increased expression of insulin-like growth factor binding protein 5 (IGFBP-5) in scleroderma fibroblasts and fibrotic lung tissue from patients with idiopathic pulmonary fibrosis. Furthermore, over-expression of IGFBP-5 in vitro and in vivo results in aberrant extracellular matrix (ECM) production, a hallmark of fibrotic disease. IGFBP-5 induces expression of the major extracellular matrix proteins fibronectin and collagen I. Additionally, there is reduced expression of the Hsp70 heat shock protein both in vivo in lung tissue and primary fibroblasts from patients with SSc-associated pulmonary fibrosis and in vitro in response to lGFBP-5 over-expression. We hypothesize that IGFBP-5 increases production of matrix structural proteins through Hsp70-dependent pathways, thereby disrupting ECM homeostasis and resulting in fibrosis.
The specific aims of this proposal are to (1) identify the mechanism of lGFBP-5 mediated ECM imbalance, (2) characterize the regulation of Hsp70 by IGFBP-5, and (3) characterize the role of Hsp70 and the heat shock transcription factors in the regulation of ECM deposition. Biochemical and genetic in vitro studies in primary mouse and human lung fibroblasts will elucidate signaling pathways and transcription factors involved in lGFBP-5's regulation of Hsp70 and the ECM, as well as in regulation of ECM production by heat shock proteins and transcription factors. Complementary in vivo work will be conducted in a mouse model of IGFBP-5 over-expression in the lung. In total, these studies will provide mechanistic insight into the IGFBP-5 pro-fibrotic cascade and the role of the heat shock response in ECM deposition, leading to an enhanced understanding of the derangements in extracellular matrix homeostasis that lead to fibrosis.
The interstitial lung diseases (ILDs) result in significant morbidity and mortality, and there are no effective medical therapies to reverse fibrosis. The proposed investigations will not only serve to define how lGFBP-5 and Hsp70 affect extracellular matrix balance, but will also provide better insight into the mechanisms of fibroproliferative diseases in the lung and serve as a foundation for the development of novel diagnostic and therapeutic strategies for the ILDs.