Kevin P. Rosenblatt, M.D., Ph.D.
My main focus of interest is in the discovery and validation of biomarkers and novel drug targets for molecular pathways of disease in animal and cell models and in human biological fluids and tissues. Mostly, I have focused on protein-based biomarkers and molecular targets because proteins are the "workhorses" of cells and tissues--i.e. proteins carry out the majority of the cell signaling and metabolic reactions necessary for normal physiology, and deranged protein networks are responsible for altered metabolism that results in disease. Thus, while studying the mutations of key genes in the genome and how these mutations effect gene expression at the message level is incredibly useful for understanding the molecular basis of many diseases, a knowledge of how protein expression is altered--which proteins, their relative levels, and their altered regulation at the post-translational level--is necessary for a more complete understanding of a disease process.
A cell's proteome (a complete description of protein expression and regulation for a cell) is more complex than its genome: Each protein species derived from an alternative spliceform of a gene or from an alternate post-translational modification, and proteins in complex with with different proteins as a multimeric complex, and indeed proteins that exist in different conformational states, may all exhibit a discrete activity that may yield valuable information; the sum of these possibilities is far greater than the total number of genes in the genome. Because of the vast chemical and structural complexity of the proteome, then, it is important to develop technologies that have reasonable throughput and suitable dynamic range (for example, the dynamic range of protein expression levels may be as high as 1011 to 1014 in the blood) for protein target discovery. Thus, my group has been engaged in the development of technologies that facilitate protein marker discovery and technologies by which tentative targets can be validated. Many of our initial studies have been directed towards human fluids and tissues for the direct discovery of human markers and therapeutic targets; these types of studies depend on a close collaboration and interaction with clinicians, chemists, technologists, biologists, informaticists, and statisticians. Therefore, we envision the Sealy Center for Molecular Medicine as an appropriate center of activity for these types of clinically oriented studies.
We have also worked out high-throughput screening methodologies, including phospho-proteomic lysate microarrays, for dissecting cell signaling pathways (e.g. MAPK and and transcriptional activators) that drive signaling in diseased cells, such as cancer cells. These functional genomic approaches can lead to the selection of druggable candidates and suitable signaling profiles that distinguish one disease sub-classification from another--useful tools in this new era of personalized molecular medicine. Future projects include the design of high-content imaging assays for protein expression- and morphologically-based biomarker and drug target discovery.
Finally, because animal and cell line models are still a useful way to gain insight to human diseases and cellular physiology, we work in collaboration with basic research groups to apply the above methodologies to such models to discern candidates that may be relevant to human disease. We then attempt to translate these findings into human diseased tissues and biological fluids to determine relevance for the human disease correlates. Along these lines, we have been using proteomic and functional genomic techniques to dissect the protein networks driving Klotho protein signaling cascades: Klotho is a novel protein family member that has been implicated in aging/longevity and oxidative stress pathways in mammals. Klotho is a single pass transmembrane protein, expressed in limited tissues, that is released and circulates in the blood and CSF and has potentially far reaching effects on cellular metabolism. Recent efforts and publications have concerned the identification of the Klotho "receptor" and some of the cytoplasmic and nuclear signals of Klotho activity and their biological consequences; we are now engaged in translational projects to determine the role of this protein, if any, in human aging and in human age-related diseases such as Parkinson Disease and in cancer. Studies such as these may increase our understanding of cancer pathogenesis and neurodegeneration and suggest novel approaches to therapies.
