Two young investigators in the University of Cincinnati (UC) College of Medicine’s Cancer Biology Department have received R01 and R35 grants from the National Institutes of Health to help them further basic research on mechanisms that cause the formation of certain cancers. The findings are important steps in developing therapies that could one day help patients live a fuller, longer life.
These major grants—totaling about $3.5 million over five years—are a true testament to the important work that goes on in cancer research at UC, says Jun-Lin Guan, PhD, Francis Brunning Professor and Chair of the Department of Cancer Biology at the UC College of Medicine and member of both the Cincinnati Cancer Center and UC Cancer Institute.
"In an environment where federal funding is difficult to obtain, we have secured these grants to further work in combating cancer,” he says. "It is quite an accomplishment to see two of our newer, younger faculty members achieve this support from the NIH. The work they are doing to study the underlying causes of cancers, both rare and common, is impacting the future treatment of patients, and they deserve this recognition, as it is changing and shaping the field.”
Guan adds that important mentorships within the department and across the college have helped these faculty members achieve this milestone in their careers while at UC.
"Our continued efforts to recruit outstanding new faculty and provide them with a supportive and intellectually stimulating research environment and outstanding infrastructure will be crucial to sustain and grow our research excellence in the department and across the college, particularly for our National Cancer Institute designation aspiration,” he says.
The projects and principal investigators are:
Chenran Wang, PhD, assistant professor, studying the molecular pathways that cause a rare genetic, tumor-forming condition to develop
"Tuberous sclerosis complex (TSC) is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs; it affects as many as 50,000 people in the U.S. TSC can also affect the brain by causing seizures, autism and intelligence instability in newborns and adults. The mutations of genes known as Tsc1 or Tsc2 lead to the loss of their tumor suppressing functions which control the activity of mTORC1, a protein complex, and its abnormal function in the formation of TSC. mTORC1 is an established "master regulator” of cells and stimulates the activity of cell growth but negatively regulates autophagy, in which a cell basically eats itself. Our recent findings revealed a higher autophagy activity in Tsc1-deficient cells under energy stress conditions, leading to the production of a novel double knockout animal model, where TSC1 and FIP200, an essential autophagy protein, were deleted in the neural (nervous system) stem cells (NSC). Using this unique model, we revealed the essential functions of autophagy to sustain high mTORC1 activity and in abnormal development of Tsc1-deficient NSC. These pilot findings lead us to believe that autophagy plays a major role in the ability of NCS to maintain high mTORC1 activity and provides a metabolic target for TSC patients. In this study, we will examine the molecular and metabolic mechanisms of autophagy in regulating signaling pathways for high mTORC1 activity, using Tsc1-deficient NSC. We will also use our newly developed FIP200 knock in model—meaning we only eliminated autophagy activity of this protein genetically while preserving the protein itself—to further clarify the mechanisms in Tsc1-deficient animals. We will also adopt pharmacological methods to target autophagy and its mediated metabolism to treat defects in Tsc1-deficient NSC. This will help us expand our knowledge of pathogenesis in TSC-deficient NSC, identify signaling pathways and metabolic alterations by hyper activating mTORC1 and develop new therapeutic concepts for continued investigation in the treatment of TSC patients.”
Jiajie "JJ” Diao, PhD, assistant professor, studying how a cells’ ‘recycling system’ impacts the development of certain conditions and how it could be targeted for treatment
"Autophagy, in which a cell basically eats itself, is a crucial pathway by which cellular waste is recycled. Autophagic dysfunction has been associated with cellular quality control, responses to stress, development, lifespan and a range of infectious and other diseases in humans, including cancer, neurodegenerative diseases and diabetes. Membrane fusion—a fundamental process in life where two separate lipid membranes merge into a single continuous bilayer—is a critical process involved in the formation of an autophagic membrane, otherwise known as autophagosome biogenesis. However, the exact molecular mechanism of autophagic membrane fusion remains clear, and thus, a major topic of investigation. Since membrane fusion activity could act as a switch to regulate the autophagy in human diseases due to its abnormal regulation, dissecting the fusion machinery is essential to understanding the exact roles of autophagy in specific disease contexts. Therefore, studying the regulatory mechanism of membrane fusion will provide the opportunity to develop new therapeutic strategies in order to control activity of autophagy. Based on our preliminary findings, we think that the modification of autophagic SNAREs (proteins) are important for controlling membrane fusion involved in autophagosome biogenesis, while this process is regulated by other proteins including nuclear receptor binding factor 2 and Atg9. Further studies on the role of SNARE-controlled membrane fusion in the formation of the autophagosome and its ability to begin working are critical to understanding detailed molecular mechanisms, which could offer therapeutic advances. Additionally, an attempt to find new fusogens, proteins that facilitate the fusion of cell to cell membranes, and reconstruct the early autophagosome biogenesis is an important expansion, which is also essential for future drug development.”