As an optical engineer and laser spectroscopist, my long-term career goal is to become a productive biophysicist with the expertise to apply advanced optical techniques to the study biomedical problems. Based on my previous physical science training and current research interests, my research focuses are 1) applying advanced microscopy techniques to understand novel protein-protein, protein-lipid interactions, trafficking and signaling pathways which are important in elucidating the pathogeneses and developing new treatments for phosphate and glucose disorders that are common in chronic kidney disease and in diabetes, and 2) developing advanced microscopy and imaging techniques that are especially designed to study protein interactions, protein signaling pathways, trafficking and lipi nanodomain (lipid raft) interactions in living cells. An advisory committee will be formed including six world-renowned experts both in bioscience and advanced microscopy techniques to provide me abundant support and technical advice during the entire training period. A five-year training plan includes a three-years mentored research period and a two-years independent research period designed to 1) build a broad background in cell biology, renal and intestinal physiology;and 2) apply and develop new advanced microscopy techniques that are strongly relevant to study protein-protein, protein-lipid interactions and protein signaling pathways. The bioscience training strategy includes a) didactic training (5 courses, 25 credit hours) in cell biology, b) journal reading in renal physiology, c) biochemistry and cell biology laboratory training and d) bioscience conference and meeting attendance. The advanced microscopy training strategy includes a two month per year visit to the Laboratory for Fluorescence Dynamics at the University of California, Irvine to develop advanced microscopy techniques and to apply the latest microscopy techniques to bioscience studies. The type II sodium gradient-dependent phosphate (NaPi) cotransport proteins are the molecules responsible for reabsorption of phosphate (Pi) both in the kidney and in the gut. However, the regulatory pathways of renal and intestinal Pi transport are still largely unknown. A better understanding of the dynamic regulation of the NaPi cotransporters, their interacting regulatory proteins, and the local lipid microdomain (lipid raft) environment is critical to finding new treatment strategies for various diseases, including chronic kidney disease, atherosclerosis and vascular clarification, which are associated with the imbalance of plasma Pi concentration. Recently, we have demonstrated that the cholesterol-sensing nuclear hormone receptor, Liver X Receptor (LXR) plays an active role in Pi regulation. The renal and intestinal NaPi transporter activity and abundance are significantly reduced after treatment with LXR agonists. In this proposal, we intend to study the NaPi protein dynamics, NaPi-PDZ domain proteins, and NaPi- lipid interactions under baseline conditions and following treatments with LXR agonists in living renal and intestinal cells using advanced fluorescence dynamics microscopy techniques. These techniques include fluorescence cross-correlation spectroscopy (FCCS), cross-correlation raster image correlation spectroscopy (ccRICS), number &brightness (N&B) analysis, fluorescence resonance energy transfer (FRET), lifetime imaging, and molecular tracking (MT) techniques. These techniques allow for direct measurements of NaPi protein dynamics, NaPi-PDZ domain proteins, and NaPi-lipid interactions in living cells that can shed significant light on the regulaory pathways of Pi homeostasis. In addition, during the last two years of independent research period, sodium-gradient dependent glucose transporters (SGLT) will be studied to understand protein-protein interactions with PDZ domain proteins and protein-lipid interactions in glucose regulation using the above mentioned advanced microscopy techniques to establish my research independency.
The major goal of this project is to apply advanced microscopy techniques to study protein-protein and protein-lipid interactions of the sodium gradient-dependent phosphate and glucose cotransport proteins (NaPis and SGLTs), their supporting proteins and the lipid nanodomains (rafts) under the influence of various physiological relevant conditions in live renal and intestinal cells.
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