Qian Shi, Ph.D.

I am a research faulty in Dr. Manzoor Bhat’s laboratory. I’ve been focused on investigating the pathophysiological mechanisms underlying metabolic disorders, such as diabetes and cancer. There is strong evidence suggesting that the incidence of several types of cancer is increased in patients with diabetes, including leukemia, kidney cancer, colon cancer, and etc. We are particularly interested in the signaling pathways that link cancer and diabetes, among which are the mTOR signaling pathways and reactive oxygen species (ROS).  The mammalian target of Rapamycin (mTOR) is a central player in governing the cellular growth and metabolic homeostasis in response to many growth factors, cellular energy status, and amino-acid levels. The mutations on either TSC1 or TSC2 genes (that regulate mTOR) leads to a rare, multi-system genetic disorder, named tuberous sclerosis complex (TSC), that cause benign tumors to grow in the brain and on other vital organs such kidneys, heart, eyes, lungs, and skin. Because of the ineffectiveness of Rapamycin (inhibitor for mTORC1) in treating TSC, it’s worthy to investigate the alternative therapeutic options as the signaling pathways are not fully understood.

1. The role of mTOR signaling in myelinating glia

TSC severely affects neuronal function, both in CNS and PNS, leading to cognitive impairment, epilepsy, autism, and white matter abnormalities. However, its role in the process of myelination and associated CNS/PNS disorders remains to be fully understood. TSC mutated mice showed reduced myelination, disrupted paranodal domains in myelinated axons, and disorganized unmyelinated Remak bundles. We are particularly interested in elucidating the signaling pathways that linked mTOR to keys molecules in oligodendrocytes development, such as RNA–binding protein Quaking (Qk) and the 155 kDa glial Neurofascin (NfascNF155). This will help design the new generation of inhibitors for treating TSC.

2. The role of mTOR/Nox4 in diabetic nephropathy

The current project aims to investigate the basic molecular mechanism that leads to the understanding of roles of renal proximal tubular epithelial cells in diabetes and in particular diabetic nephropathy (DN), one of the major complications of type 1 diabetes, and provide the novel therapeutic options. We found that high glucose up-regulates Nox4 expression in kidney, enhances NADPH oxidase activity and up-regulates fibronectin. Moreover, high glucose activates the mTOR pathway through enhancing mTORC1/2 activity. However, the precise mechanism by which mTORC2 regulates Nox4 expression/activation is still unknown. We are currently utilizing in vitro and in vivo approaches to establish the importance of possible mTORC2/Nox4 signaling pathway in mediating tubular epithelial cell injury in the diabetic environment, hoping to provide new therapeutic options for treating DN.