Morsani College of Medicine
Department of Molecular Medicine
Joint and Affiliate Faculty
Post-Doctorates / Research Associates
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Master's of Science Program
Allergy, Immunology and Infectious Diseases
USF Health Byrd Alzheimer's Institute
Children's Research Institute (CRI)
Center for Drug Discovery and Innovation
H. Lee Moffitt Cancer Center
James A Haley Veteran's Hospital
Bay Pines VA Healthcare System
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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Graduate Research Assistant, College Of Medicine Molecular Medicine
My Ph.D. research topic focuses on hepatocyte stages of Plasmodium berghei and novel drug development against the increasing resistance against current treatments for malaria as well as the lack of drugs targeting liver stage parasites. Elucidation of the mechanism of action of these discovered drugs and their targets are some of the many goals of my thesis.
Postdoctoral Scholar Research, College Of Medicine Molecular Medicine