The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases

 Kevin Rosenblatt, M.D., Ph.D.

Kevin Rosenblatt, M.D., Ph.D.

Associate Professor, Center for Proteomics and Systems Biology

Kevin.Rosenblatt@uth.tmc.edu

(713) 500-3611

Dr. Rosenblatt graduated cum laude from Tulane University, New Orleans, Louisiana with a double major in Chemistry and Judaic Studies. He then graduated from the Medical Scientist Training Program at UT Southwestern in June of 2000 where he earned both a Graduate degree in the Department of Cell Biology and Neuroscience and a Medical degree. His graduate studies required the development of several novel and technically challenging molecular techniques (e.g. in situ, exon-specific, RT-PCR) which lead to a cover article in Neuron. During his senior year in medical school, he was awarded the Stembridge Award for Excellence in Pathology for his medical school academic achievements and research accomplishments. At the NIH in Bethesda, Maryland, Dr. Rosenblatt completed the Anatomic Pathology Residency Training Program and then a Clinical Research Fellowship in Clinical Proteomics within the FDA-NCI Clinical Proteomics Program. During his residency, he changed his research focus from the neurosciences to the discovery of genomic and proteomic biomarkers for the diagnosis and management of cancer. He was then recruited by the Department of Pathology at the University of Texas Southwestern Medical School as the Associate Director of the Division of Translational Pathology in November 2003. There, he was founder and Co-Director of the UT Southwestern Tissue Repository (UTSTR), a comprehensive tissue bank concentrating on the collection of human clinical samples, and Director of the Clinical Proteomics Program.

Before coming to the IMM, Dr. Rosenblatt held a joint appointment as Associate Professor in the Department of Biochemistry and Molecular Biology and the Department of Internal Medicine at UTMB. There he also held a position as Scientist and Director of Biomarker Development in the Sealy Center for Molecular Medicine; Project Leader for Biomarker Discovery in the NHLBI Proteomics Center; and Director of Biomarker Verification for the NIAID Clinical Proteomics Center for Emerging Infectious Disease and Biodefense.

Dr. Rosenblatt joined the IMM faculty as Associate Professor of Molecular Medicine, with a secondary appointment in the Department of Pathology and Laboratory Medicine within the UT Health Science Center Houston School of Medicine; he also has an affiliation with the Department of Obstetrics, Gynecology and Reproductive Sciences. He is Director of the Center for Clinical Proteomics in the new Centers for Proteomics and Systems Biology directed by Dr. David Gorenstein, and he is Co-Director of the UT-HSC Center for Clinical and Translational Sciences Proteomics Core Laboratory.

Research Interests:

Dr. Rosenblatt's 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, his group has 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 messenger RNA 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 posttranslational 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 posttranslational modification, and proteins in complex 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 biological and clinical 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, or up to 14 decades in measurable values, in the blood) for protein target discovery. Thus, the Rosenblatt lab 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, Dr. Rosenblatt envisions the Brown Foundation Institute for Molecular Medicine as an appropriate center of activity for these types of clinically oriented studies.

Dr. Rosenblatt's group has 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 subclassification 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's Disease and in cancer. Studies such as these may increase our understanding of cancer pathogenesis and neurodegeneration and suggest novel approaches to therapies.

NIAID and NHLBI Proteomics Centers: For the NIAID Clinical Proteomics Center, Dr. Rosenblatt has set up several protein microarray platforms for high-throughput verification and validation of markers within nanoliters to microliters of cell lysate material or biological fluids. These innovative technologies include a quantum dot-based reverse phase array platform for analyzing over 10,000 samples in triplicate per microchip and several multiplexed array-based ELISA platforms suitable for rapid analysis of clinical and research samples. His work for the NLHBI Proteomics Center is more discovery based: using several emerging mass spectrometry and micro/nano-flow chromatography dependent systems to find novel protein markers and drug targets within cells, tissues, and biofluids. Using such techniques, Dr. Rosenblatt has discovered several regulatory pathways downstream of Klotho activation. The Klotho gene produces a protein that regulates endogenous anti-oxidant proteins and modulates several important signaling pathways including the Wnt, IGF-1, FGF, insulin, and TGF-beta signaling pathways; Klotho activation prolongs life when over expressed and leads to rapid early aging when reduced in expression in mouse models. He has found through proteomics and functional genomics experiments that the Klotho protein also confers protective effects on the brain, kidneys, heart, and other organs when over-expressed in these models.

Publications:

Research Articles

1. Oh, J.H., Lotan, Y., Gurnani, P., Rosenblatt, K.P., and Gao, J. (2008) Prostate cancer biomarker discovery using high-performance mass spectral serum profiling. Computer Methods and Programs in Biomedicine, in press (Co-Senior Author).

2. Tan, N.C., Fisher, W., Rosenblatt, K.P., and Garner, H.R. (2009)

Application of multiple statistical tests to enhance mass spectrometry-based

biomarker discovery. BMC Bioinformatics 10: 144 (on-line; in press).

3. Rosenblatt, K.P., Huebschman, M.L., and Garner, H.R. (2009) Construction and Hyperspectral Imaging of Quantum Dot Lysate Arrays. Methods in Molecular Biology, in press.

4. Huebschman, M.L., Rosenblatt, K.P., and Garner, H.R. (2009) Hyperspectral microscopy imaging to analyze pathology samples with multi-colors reduces time and cost. Proceedings of SPIE, BiOS 2009, in press.

5. Kempe, D.S., Ackermann, T.F., Fischer, S.S., Koka, S., Boini, K.M., Mahmud, H., Föller, M., Rosenblatt, K.P., Kuro-o, M., and Lang, F. (2009) Accelerated suicidal erythrocyte death in Klotho-deficient mice. Pflugers Archiv-European Journal of Physiology, in press.

6. Kim, Y.B., Oh, J.H., Rosenblatt, K.P., and Gao, J. (2009) Biological data outlier detection based on Kullback-Leibler divergence.  Proceedings of the IEEE International Conference on Bioinformatics and Biomedicine (IEEE BIBM) 2008, in press.

7. Oh, J.H., Gurnani, P., Schorge, J., Rosenblatt, K.P., and Gao, J. (2009)  An extended Markov blanket approach to proteomic biomarker detection from high-resolution mass spectrometry data. IEEE Transactions on Information Technology in Biomedicine 13: 195-206.

8. Cha, S.-K., Ortega, B., Kurosu, H., Rosenblatt, K.P., Kuro-o, M., and Huang, C.-L. (2008)  Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via a binding to galectin-1. Proceedings of the National Academy of Sciences (USA) 105: 9805-9810.

9. Oh, J.H., Kim, Y.B., Gurnani, P., Rosenblatt, K.P., and Gao, J. (2008)  Biomarker selection and sample prediction in multi-category disease on MALDI-TOF data. Bioinformatics 24: 1812-1818.

10. Oh, J.H., Kim, Y.B., Gurnani, P., Rosenblatt, K.P., and Gao, J. (2007)  A novel classification method for analyzing multi-stage diseases using MALDI-TOF mass spectra. Proceedings of the IEEE International Conference on Bioinformatics and Biomedicine (IEEE BIBM) 2007: 237-242  (Co-Senior Author).

11. Oh, J.H., Kim, Y.B., Gao, J., Nandi, A., Gurnani, P., and Rosenblatt, K.P. (2007)  Biomarker selection in Alzheimer disease using high-resolution MALDI-TOF data. Proceedings of the 7th IEEE Symposium on Bioinformatics and Bioengineering (IEEE BIBE) 2007: 464-471, 14-17 October 2007 (Co-Senior Author).

12. Fisher, W.G., Rosenblatt, K.P., Fishman, D.A., Whiteley, G.R., Mikulskis, A., Kuzdzal, S.A., Lopez, M.F., and Garner, H.R. (2007) A robust biomarker discovery pipeline for high-performance mass spectrometry data. Journal of Bioinformatics and Computational Biology 5: 1023-1045.

13. Kurosu, H., Choi, M., Ogawa, Y., Dickson, A.S., Goetz, R., Eliseenkova, A.V., Mohammadi, M., Rosenblatt, K.P., Kliewer, S.A., and Kuro-o, M. (2007) Tissue-specific expression of βKlotho and fibroblast growth factor receptor isoforms determines metabolic activity of FGF19 and FGF21. Journal of Biological Chemistry 282: 26687-26695 (Accelerated Publication; On-Line July 10, 2007).

14. German, D.C., Gurnani, P., Nandi, A., Garner, H.R., Fisher, W.G., Diaz-Arrastia, R., O'Suilleabhain, P., and Rosenblatt, K.P. (2007)  Serum biomarkers for Alzheimer's disease: Proteomic identification. Biomedicine and Pharmacotherapy 61: 383-389 (On-Line June 18, 2007).

15. Lopez, M.F., Mikulskis, A., Kuzdzal, S., Golenko, E., Petricoin III, E.F., Liotta, L.A., Patton, W.F., Whiteley, G.R., Rosenblatt, K.P., Gurnani, P., Nandi, A., Neill, S., Cullen, S., O'Gorman, M., Sarracino, D., Lynch, C., Johnson, A., Mckenzie, W., Fishman, D. (2007)  A novel, high-throughput workflow for discovery and identification of serum carrier protein-bound peptide biomarker candidates in ovarian cancer samples. Clinical Chemistry  53: 1067-1074 (on-line April 26th, 2007).

16. Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K.P., Goetz, R., Eliseenkova, A.V., Mohammadi, M., and Kuro-o, M. (2007)  βKlotho is required for metabolic activity of fibroblast growth factor-21. Proceeding of the National Academy of Sciences (USA) 104: 7432-7437 (on-line April 23rd, 2007).

17. Rosenblatt, K.P. and Kuro-o, M. (2007) Klotho, an Aging-Suppressor Gene. Hormone Research 67 Suppl 1: 191-203.

18. Geho, G.H., Killian, J.K., Nandi, A., Pastor, J., Gurnani, P., and Rosenblatt, K.P. (2007)  Fluorescence-based analysis of cellular protein lysate arrays using quantum dots.  Methods in Molecular Biology 374: 229-238.

19. Oh, J.H., Nandi, A., Gurnani, P., Knowles, L., Schorge, J., and Rosenblatt, K.P., Gao, J. (2006)  Proteomic Biomarker Identification for Diagnosis of Early Relapse in Ovarian Cancer. Journal of Bioinformatics and Computational Biology 4: 1159-1179 (Co-Senior Author).

20. Oh, J.H., Nandi, A., Gurnani, P., Knowles, L., Schorge, J., Rosenblatt, K.P., and Gao, J. (2006) A hybrid feature selection tool for MALDI-TOF mass spectrometry data analysis. Proceedings of IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology (IEEE CIBCB) 2006: 36-43, 28-29 September 2006,Toronto, Ontario, Canada (Co-Senior Author).

21. Oh, J.H., Nandi, A.,  Gurnani, P., Bryant-Greenwood, P., Rosenblatt, K.P., and Gao, J. (2006) Prediction of labor for pregnant women using high-resolution mass spectrometry data. Proceedings of the Sixth IEEE International Symposium on BioInformatics and BioEngineering (BIBE BIBE) 2006: 332-339, 16-18 October 2006, Arlington, Virginia, USA (Co-Senior Author).

22. Srinivasan, R., Daniels, J., Fusaro, V., Lundqvist, A., Killian, J.K., Geho, D., Quezado, M., Kleiner, D., Rucker, S., Espina, V., Whiteley, G., Liotta, L., Petricoin, E., Pittaluga, S., Hitt, B., Barrett, A.J., Rosenblatt, K.P., and Childs, R.W. (2006)  Accurate diagnosis of acute graft-versus-host disease using serum proteomic pattern analysis.  Experimental Hematology, 34: 796-801.

23. Narayan, S.B., Rakheja, D., Pastor, J.V., Rosenblatt, K.P., Greene, S.R., Yang, J., Wolf, B.A., Bennett, M.J. (2006)  Over-expression of CLN3P, the Batten disease protein, inhibits PANDER-induced apoptosis in neuroblastoma cells: Further evidence that CLN3P has anti-apoptotic properties. Molecular Genetics and Metabolism, 88: 178-183 (March 1st early access).

24. Kurosu, H., Ogawa, Y., Miyoshi, M., Yamamoto, M., Nandi, A., Rosenblatt, K.P., Baum, M.G., Schiavi, S., Hu, M.-C., Moe, O.W., and Kuro-o, M. (2006)  Regulation of fibroblast growth factor-23 signaling by Klotho. Journal of Biological Chemistry, 281: 6120-6123 (Accelerated Publication).

25. Oh, J., Gao, J., Nandi, A.,  Gurnani, P., Knowles, L., Schorge, J., and Rosenblatt, K.P. (2005)  Multicategory classification using extended SVM-RFE and Markov blanket on SELDI-TOF mass spectrometry data. Proceedings of the IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology (IEEE CIBCB) 2005: 339-345, 14-15 November 2005, San Diego, California, USA.

26. Oh, J.H., Gao, J., Nandi, A., Gurnani, P., Knowles, L., Schorge, J., and Rosenblatt, K.P. (2005) Diagnosis of early relapse in ovarian cancer using serum proteomic profiling. Genome Informatics (Genome Informatics Workshop 2005) 16: 195-204.

27. Yamamoto, M., Clark, J.D., Pastor, J.V., Gurnani, P., Nandi, A., Kurosu, H., Miyoshi, M., Ogawa, Y., Castrillon, D.H., Rosenblatt, K.P., and Kuro-o, M. (2005)   Regulation of oxidative stress by the anti-aging hormone Klotho.  Journal of Biological Chemistry 280: 38029-38034 (JBC Paper of the Week).

28. Kurosu, H., Yamamoto, M., Clark, J.D., Pastor, J.V., Nandi, A., Gurnani, P., McGuinness, O.P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., Shimomura, I., Takayama, Y., Herz, J., Kahn, C.R., Rosenblatt, K.P., and Kuro-o, M. (2005)   Suppression of aging and insulin/insulin-like growth factor-1 signaling by the hormone Klotho.  Science 309: 1829-1833 (in SciencExpress August 25, 2005).

29. Geho, D., Lahar, N., Gurnani, P., Huebschman, M., Herrmann, P., Espina, V., Shi, A., Wulfkule, J., Garner, H., Petricoin III, E.F., Liotta, L.A., and Rosenblatt, K.P. (2005)  Pegylated, Streptavidin-Conjugated Quantum Dots are Effective Detection Elements for Reverse Phase Protein Microarrays.  Bioconjugate Chemistry 16: 559-566.

30. Espina, V., Mehta, A.I., Liotta, L.A., Petricoin III, E.F., Geho, D., and Rosenblatt, K.P. (2005)  Pathology of the Future: Molecular profiling for targeted therapy.  Cancer Investigation 23: 36-46.

31. Feldman, A.L., Espina, V., Petricoin III, E.F., Liotta, L.A., and Rosenblatt, K.P. (2004)  Use of proteomic patterns to screen for gastrointestinal malignancies.  Surgery 135: 243-247.

32. Carr, K.M., Rosenblatt, K.P., Petricoin III, E.F., and Liotta, L.A.  (2004)  Genomic and proteomic approaches to study human disease: Prospects for true patient-tailored therapy.  Human Genomics 1: 134-140.

33. Rosenblatt, K.P., Bryant-Greenwood, P., Killian, K.J., Mehta, A., Geho, D., Espina, V., Petricoin III, E.F., and Liotta, L.A. (2004)  Serum proteomics in cancer diagnosis and management.  Annual Review of Medicine 55: 97-112.

34. Weeraratna, A.T., Becker, D., Carr, K.M., Duray, P.H., Rosenblatt, K.P., Yang, S., Chen, Y., Bittner, M., Strausberg, R.L., Riggins, G.J., Wagner, U., Kallioniemi, O. P., Trent, J. M., Morin, P.J., and Meltzer, P.S. (2004)  Generation and analysis of melanoma SAGE libraries: SAGE advice on the melanoma transcriptome.  Oncogene 23: 2264-2274.

35. Liotta, L. A., Espina, V., Mehta, A.I., Calvert, V., Rosenblatt, K., Geho, D., Munson, P. J., Young, L., Wulfkuhle, J., and Petricoin III, E.F. (2003)  Protein microarrays: Meeting analytical challenges for clinical applications.  Cancer Cell 3: 317-325.

36. Koch, C. A., Brouwers, F.M., Rosenblatt, K.P., Burman, K.D., Davis, M M., Vortmeyer, A.O., and Pacak, K. (2003)  Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea.  Endocrine-Related Cancer 10: 99-107.

37. Weeraratna, A.T., Jiang, Y., Hostetter, G., Rosenblatt, K., Duray, P., Bittner, M., and Trent, J.M. (2002)  Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.  Cancer Cell 1: 279-288.

38. Rosenblatt, K.P., Sun, Z.-P., Heller, S., and Hudspeth, A.J. (1997)  Distribution of Ca2+-activated K+ channel isoforms along the tonotopic gradient of the chicken's cochlea.  Neuron 19: 1061-1075.

Book Chapters

1. Rosenblatt, K.P., Michael L. Huebschman, M.L., and Garner, H.R. (2009) Construction and Hyperspectral Imaging of Quantum Dot Lysate Arrays. In Methods of Molecular Biology: Individualized Molecular Medicine. Espina, V. and Liotta, L.A., eds. (Totowa: Humana Press, Inc.), in press.

2. Geho, G.H., Killian, J.K., Nandi, A., Pastor, J., Gurnani, P., and Rosenblatt, K.P. (2007)  Fluorescence-based analysis of cellular protein lysate arrays using quantum dots. In Methods of Molecular Biology: Quantum Dots in Biology. Hotz, C. and Bruchez, Jr., M., eds. (Totowa: Humana Press, Inc.), pp 229-238.

3. Shimizu, C., Rosenblatt, K.P., and Bryant-Greenwood, P.K. (2006)  Clinical Proteomics.  In Prenatal Diagnosis. Evans, M.I., Johnson, M.P., Yaron, Y., and Drugan, A., eds.   (New York: McGraw Hill), pp 513-522.