Ting Dong, PhD | Chinese Academy of Medical Sciences; Ruijuan Gao, PhD
Competition Sponsor: Chinese Academy of Medical Sciences
Awardee Year: 2025
Confronting the severe challenge of accelerating global population aging, aging-associated pulmonary fibrosis presents a critical dual public health threat, while existing therapeutics such as pirfenidone and nintedanib only slow disease progression without reversing fibrosis; this underscores an urgent need for breakthrough therapies targeting core pathological mechanisms with dual anti-aging and anti-fibrotic efficacy. Building upon our original discovery that disrupted vimentin proteostasis constitutes a central driver of fibroblast senescence and pulmonary fibrosis—wherein aberrant aggregation compromises cytoskeletal integrity and induces profibrotic secretory phenotypes—this project aims to develop innovative strategies targeting proteostasis regulation. We employ a dual-track approach integrating chemical and classical genetics: firstly, optimizing lead compound 9-85 to develop molecules that selectively degrade pathogenic vimentin aggregates while elucidating their mechanism involving CCT2 recruitment for autophagic clearance; secondly, deciphering the cooperative mechanism by which the Calumenin-TRiC (TCP-1 ring complex) chaperonin complex promotes vimentin correct folding to reveal the pathological cascade of aberrant aggregation. Integration of both tracks will map the dynamic vimentin folding-degradation regulatory network, yielding 1-2 preclinical candidate compounds capable of reversing fibrosis and cellular senescence, generating 1–2 core patents, and pioneering the world’s first proteostasis-targeting anti-aging therapy. The project leverages robust preliminary foundations, including our team’s validation of vimentin aggregation’s pathogenic role, active compound 9-85 with established structure-activity relationship (SAR) data, and dedicated platforms for proteostasis research, aging-associated pulmonary fibrosis animal models, and clinical specimen biobanks, providing comprehensive support to overcome current therapeutic limitations.