Research Statement: Genetic Control of Aging by Sestrin-TOR Network
by Jun Hee Lee
Previously, I investigated genetic programs governing diverse animal physiologies using Drosophila and mice as model organisms. Specifically, I focused on several key signaling pathways that control growth, aging, differentiation, innate immunity, inflammation, apoptosis and cell polarity. For my Ph.D. thesis, I studied the function of p53 and LKB1, two tumor suppressors frequently mutated in human cancers. Using p53-null flies, one of the first models lacking all p53 function, I confirmed the role of p53 in DNA damage-induced apoptosis and maintenance of genomic stability. In addition, through fly genetic screening, I found that JNK mediates LKB1-induced apoptosis. Subsequent studies led me to make a more striking finding that AMPK, a downstream kinase of LKB1, is mediating energy-dependent regulation of cell shape. This work was published in Nature.
As a postdoc in Dr. Karin’s lab at UCSD, I focused on Sestrins, novel stress-inducible molecules regulated by p53. Utilizing my expertise in Drosophila and p53/AMPK/TOR signaling, I was able to reveal the novel role for Sestrin as a feedback regulator of TOR signaling (Fig. 1), which attenuates diverse age- and obesity-associated pathologies such as cancerous cell growth, fat accumulation, muscle degeneration and cardiac malfunction. I also suggested that the pathologies partially result from defective ATG1-mediated autophagy and diminished clearance of dysfunctional
mitochondria, protein aggregates, and lipids (Fig. 2A). This work was published in Science as the cover story article. In parallel with the Sestrin project, I was involved in another project that investigates the relationship between obesity and liver cancer, and found that inflammatory cytokine signalings are critical for obesity promotion of liver pathologies, such as hepatosteatosis, steatohepatitis and hepatocellular carcinoma. This study was published in Cell with me as a second author. In subsequent studies, I found that mammalian Sestrin 2 is functioning to
attenuate the obesity-induced metabolic derangements in mouse liver.
My planned research is a logical extension of my past and current interests. First, I will continue focusing on the role of Sestrins in suppressing diverse pathologies that are associated with obesity and aging, using Sestrins-KO and transgenic mice (Table 1) and mouse models of cancer, metabolic diseases, neurodegeneration, cardiac arrhythmia and
muscle degeneration (Fig. 2B). Considering that Sestrins are stress-inducible proteins, these studies may reveal a potential role of Sestrin in mediating hormesis, a paradoxical beneficial effects of low-level stresses (Fig. 3). At the same time, using phospho-proteomics and genome-wide RNAi screening in Drosophila cells, I will identify new genetic components that mediate ATG1-dependent control of autophagy and autophagic removal of damaged mitochondria (Fig. 4), which are critical for preventing aging and associated pathologies. Then, using Drosophila genetics, I will characterize the biological roles of newly isolated genetic components. Following these foundation-building experiments, I will embark on long-term mouse experiments on the molecules and related hypotheses. Being well versed with both Drosophila and mouse systems, I will be able to conduct the two-pronged approaches for each individual research project, and this dual strategy will increase the effectiveness of my research program and allow me to decipher the fundamental genetic mechanisms of growth and aging that are encoded in our genome.