Pathomechanistic role of autophagy in the development of lung fibrosis

• Applicant: Poornima Mahavadi, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 286482838

Autophagy is a fundamental biological process of a cell. The term autophagy literally means self-eating and it has been known for several decades as an adaptation to starvation and as a major pathway responsible for the turnover of long-lived proteins to maintain cellular homeostasis in a lysosome dependent manner. Altered autophagy has been indicated in the pathogenesis of many devastating diseases like cancer, neurodegenerative diseases including Alzheimers disease, Parkinsons disease and in lung diseases like chronic obstructive pulmonary disease and cystic fibrosis. Regulation of autophagy in lung fibrosis represents an emerging field of research. Under conditions of lung fibrosis, insult to alveolar epithelial type II pneumocytes is known to be a major pathological event. Our preliminary data indicate dysregulation of autophagy within the alveolar epithelial cells in several forms of lung fibrosis which include mouse models of amiodarone and bleomycin induced lung fibrosis, Hermansky-Pudlak syndrome associated lung fibrosis and idiopathic pulmonary fibrosis (IPF). In this proposal, we aim to undertake the following objectives in amiodarone model of lung fibrosis as well as in IPF: 1) comprehensively analyze all autophagy pathways in detail, 2) to study the cellular fate after an experimental loss of function (exploiting the knockout mice and gene knockdown experiments) and gain of function (through over expression studies) of certain important autophagy related genes in order to identify the most important autophagy related genes and /or proteins that are decisive for driving the disease and 3) to study the role of autophagy with regard to secretory function of alveolar epithelial cells in order to unveil the still unknown basic functions of the autophagy pathway in secretory cells which will contribute towards understanding the mechanisms behind dysregulated autophagy pathway under conditions of lung fibrosis. Altogether, these studies will significantly extend our understanding regarding the importance of autophagy in the pathological chain of events in lung fibrosis and might help to design new therapeutic targets for IPF as well as for lung fibrosis induced by amiodarone.

• DFG Programme: Research Grants