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DavidKang

David Kang, PhD

Assoc Professor, COLLEGE OF MEDICINE MOLECULAR MEDICINE
  • My research focuses on the mechanisms of neurodegeneration in Alzheimer’s disease (AD) and related neurological disorders. AD is the leading cause of dementia and most prevalent neurodegenerative disease, affecting more than 40 million people worldwide. Pathologically, brains afflicted with AD are riddled with accumulations of two highly toxic proteins, namely amyloid beta and tau, which are the underlying cause of neurodegeneration. The amyloid beta protein is derived from 2 proteolytic cuts made in its precursor protein, APP, and it is widely believed that Abeta induces early neurogeneration and promotes pathology associated with the tau protein.
  • In my lab, we utilize various molecular, biochemical, cell biological, and animal modeling tools to answer important questions pertinent to healthy and pathological neuronal function. Some of these tools include confocal microscopy, fluorescence live cell imaging, calcium imaging, axonal transport of cargo proteins & organelles, generation & use of transgenic and knockout models, in vivo neurogenesis / neuronal migration assays, cell death assays, and membrane protein trafficking assays, etc. Broad questions directly relevant to our ongoing studies are the following. 1) What are the molecular pathways and therapeutic targets of Abeta generation? 2) What are the molecular pathways and therapeutic targets of Abeta-induced neurotoxicity? 3) How do Abeta-neurotoxic pathways induce synaptic damage, mitochondrial dysfunction, and tau pathology? 4) What are some naturally protective mechanisms and pathways against neurodegeneration?
  • My earlier work originally identified the genetic association of LRP, an apoE receptor, to late-onset AD. Later work by us and others found that LRP plays a dual and opposing role in APP metabolism: 1) sequestration and removal of secreted amyloid beta protein and 2) promotion of Abeta generation by increasing APP processing. We recently found that LRP is required for the majority of Abeta generation by promoting the trafficking APP to lipid rafts, cholesterol-rich intracellular microdomains highly enriched in Abeta generating proteases. We narrowed the Abeta promoting region of LRP to the C-terminal 37 residues. Using a yeast 2-hybrid screen, we identified several new proteins, which interact with the C-terminal 37 residues of LRP cytoplasmic tail (C37). One such C37 interacting protein was Ran-Binding Protein 9 (RanBP9), a multimodular scaffolding protein. We found that LRP and APP interact with each other on the neuronal surface, and RanBP9 helps to stabilize this interaction, which accelerates their internalization from the cell surface. Such endocytic event is critical for the generation of Abeta, and RanBP9 levels are highly increased in brains of AD patients and animal models of AD. We have also found that RanBP9 interacts with and helps to internalize integrins from the cell surface, thereby disrupting cell adhesions while simultaneously increasing Abeta production. On the other hand, integrins are critical for transmitting the toxic Abeta signals from the cell surface through a series of events (i.e. disruption of focal adhesions) that require RanBP9 and a downstream apoptotic / actin-binding protein, cofilin, eventually leading to the disruption of cell/synaptic integrity and mitochondrial function. Our working hypothesis based on experimental findings is that cell surface receptors and their intracellular pathways that promote the generation of Abeta are largely identical to the very pathways that transmit the neurotoxic signals induced by Abeta (i.e. integrins / LRP / APP / RanBP9 / Cofilin, etc.). In collaboration with Drs. Uversky and Chen in our department, we are also using biophysical and computational tools to structurally define various molecular targets for rational drug design in addition to the screening of compound libraries for AD therapeutics.
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Post Docs

  • The characterization of novel pan-Apicomplexa cell cycle genes.
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Ph.D. Students

  • My current research focuses on understanding the role of the Amyloid Precursor Protein (APP) in pancreatic cancer. It is well known that pancreatic cancer has a poor prognosis and very low 5-year survival rates. Early detection poses a challenge mainly owing to the location of this organ and a non-symptomatic progression. At the molecular level, the oncogene RAS is known to be mutated and overexpressed in this cancer and the signaling pathways are somewhat understood. Using several pancreatic cancer cells lines, our recent findings show that APP is overexpressed in most pancreatic cancer cells lines as well. Preliminary studies have shown that APP can regulate RAS transcription levels and knock down of APP can inhibit RAS protein expression. Using this information, my project aims to understand the mechanism of regulation of RAS by APP and to establish APP, its processed fragments, and associated signaling pathways as possible targets for drug development against pancreatic cancer.
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