Award Details:
Award Type: Catalyst
Award #: C-102
Proposal Title: Use of PROTACs to Inhibit BNIP3-dependent Mitophagy in Muscle Atrophy and Cancer Cachexia
PI(s): Kay Macleod (UChicago) and Alexis Demonbreun (NU)
Award Amount: $248,432.00
Application Cycle: Round 30 (Spring 2021)
Award Start Date: October 1, 2021
Award End Date: September 30, 2023
Abstract:
Involuntary body weight loss due to wasting of skeletal muscle is a debilitating effect of certain human cancers known as cancer cachexia. Cancer cachexia negatively affects the long-term survival of cancer patients, partly due to reduced tolerance of and response to therapy. Work proposed here will provide novel mechanistic insight to the role of mitophagy and mitochondrial dysfunction in the debilitating effects of muscle wasting during cachexia associated with pancreatic cancer. This project proposes to use proteolysis-targeting chimeras (PROTACS) to target the BNIP3 mitochondrial cargo receptor that is upregulated in cachectic muscle to limit or prevent muscle atrophy in cancer cachexia. This will be achieved by hijacking E3 Ub ligases that are upregulated in atrophying muscle to specifically degrade BNIP3 via novel PROTACs and has relevance for preventing muscle atrophy in other diseases in response to glucocorticoids or nutrient deprivation where BNIP3 is induced.