Projects and Grants
Searching for Proteomic Predictors of Disease Progression in a Subpopulation of African American Subjects with Kidney Disease.
A subset of subjects with renal disease tends to progress to renal failure/end stage disease. There are few therapies that can ameliorate the progression of the disease. We have been searching for individual proteins and/or proteomic patterns to differentiate between fast and slow progressors. To-date, five putative serum markers have been recognized. Slow progressors have consistently higher protein content than the fast ones. This suggests that the absence or low abundance of the markers may indicate the extent of progression of the disease. Identification of these markers is in progress.
Mass Spectrometric Study of Fundamental Aspects of Drug Binding to Proteins.
After observed that drug binding to proteins follows a discontinuous and interrupted digital progression, we hypothesize that the drug-binding induces distortion of the protein that occludes certain sites - which might affect the activity (function) of enzymes. We have developed a mass spectrometric technique to measure the molecular masses of intact complexes formed in the binding of anticancer agents to albumin, permitting the determination of the number of molecules bound under different experimental and clinical conditions (7, 8). In current work, we have characterized the intact complexes of serum albumin (both mouse and human) and the antineoplastic benzyl styryl sulfone analog, ON1910Na, currently in Phase I clinical trials, and demonstrated the presence of intact albumin-drug complexes in patients sera at various dose levels and at different sampling times. We are in the process of extending the technique to other, non-neoplastic drugs as well as to several major enzymes and investigation the effects of these phenomena on enzyme activity.
The aims of differential-display oncoproteomics are to find unique tumor-associated markers or to recognize proteins or protein patterns that are significantly upregulated or downregulated. A new technology, SELDI-TOF mass spectrometry, “Surface Enhanced Laser Desorption Ionization” (SELDI) combined with time-of-flight (TOF) mass spectrometry (MS) has gained acceptance as an approach to rapidly recognize and identify potential protein markers and to compare pathological and normal samples. Clinical applications of the SELDI-TOF approach now include a wide variety of cancers (reviewed in 9). Based on our recent study of putative markers to differentiate benign prostatic hyperplasia and malignant cancer (10), we are currently involved in an IRB approved pilot study to test the diagnostic usefulness of a putative serum marker of prostate cancer that is to be determined at the time of the performance of prostate biopsy.
The African American Kidney Disease project was supported by NIH NIDDK #DK67468. Our other research activities are supported by annual grants grant from the Martell Memorial Foundation. Our participation on the Phase I clinical studies of the ON 1910Na agent has been supported by Onconova, Inc.