Harvey Lodish, Ph.D.
Department of Biology
Professor of Biology and Bioengineering
Member, Whitehead Institute for Biomedical Research
Executive Director of Research, Biotech Process Engineering Center
Ph.D. Biology, 1966
Our research addresses the regulation of complex signal processing pathways in cells and their effects on biological processes. We focus on hormones, cell surface receptors and transport proteins that are involved in hematopoietic development, hematopoietic stem cells, and the regulation of glucose and fat metabolism. This work entails the development of molecular biology tools and interdisciplinary approaches such as expression cloning, immunolocalization of proteins in cells and tissues, gene-altered mice, and DNA chip analysis for transcriptional profiling of gene expression in complex signaling pathways.
Hormones controlling fatty acid and glucose metabolism
One major thrust of our work is to understand the pathways that regulate fatty acid and glucose metabolism. We cloned the mammalian glucose transporter protein, GLUT1, and we are studying how insulin signals fat cells to increase glucose uptake by moving the GLUT4 transporter to the plasma membrane. We used an expression cloning strategy based on fluorescence-activated cell sorting (FACS) to identify a new protein that participates in this insulin signaling pathway. We also cloned Acrp30, a novel protein hormone that is secreted by adipocytes and is linked genetically to development of Type II (adult-onset) diabetes. Now we are investigating the signaling pathways induced by Acrp30 as it induces fat and glucose catabolism by muscle, enhances glycogen accumulation in muscle, and inhibits gluconeogenesis in liver. Another aspect of this work focuses on the signal transduction pathways for TNF-alpha, an autocrine factor produced by adipocytes that induces insulin resistance, in part, by down-regulating Acrp30 and other adipocyte proteins involved in fat and glucose metabolism. In addition, we are examining a family of fatty acid transport proteins that we cloned, focusing on the roles of these and other proteins in lipid uptake by neuronal cells and neurite outgrowth.
Red cell development and hematopoiesis
Having cloned the receptor for the hormone erythropoietin (EpoR), we currently are investigating how this receptor prevents apoptosis of erythroid progenitor cells and induces a programmed pattern of terminal proliferation and differentiation into red blood cells. We are studying several EpoR-activated intracellular signal transduction pathways and how they coordinate red cell production. JAK2 is a cytosolic protein tyrosine kinase that is essential for EpoR signaling, and we are looking at how it binds to the EpoR cytosolic domain and becomes activated after Epo binding. An extension of this work examines the anti-apoptotic role of Epo in cells of the central nervous system.
Hematopoietic stem cells
Other projects focus on these very rare cells in the fetal liver and bone marrow. We identified a new cell-surface marker for hematopoietic stem cells and we are using it to develop new methods for purifying them. In collaboration with David Bartel laboratory, we discovered five 21-base micro RNAs specifically expressed in hematopoietic cells. Overexpression studies showed that these RNAs modulate hematopoietic lineage differentiation, and we are now elucidating the mRNAs that are regulated by these micro RNAs.
- Zhang, C-C,. M. Kaba, G. Ge, K. Xie, W. Tong, C. Hug, and H. F. Lodish. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Medicine Published online: 22 January 2006; | doi:10.1038/nm1342.
- Gross, A., and H. F. Lodish. Cellular Trafficking and Degradation of Erythropoietin and Novel Erythropoiesis Stimulating Protein NESP. J. Biol. Chem. 281 2024-2032 (2006).
- Tong, W., J. Zhang, and H. F. Lodish, Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways Blood 105: 4604 - 4612 (2005).
- Hug, C., J. Wang, N. Ahmad, J. Bogan, T.-S. Tsao, and H. F. Lodish. T-cadherin is a receptor for hexameric and high molecular weight forms of Acrp30/adiponectin. Proc. Natl. Acad. Sci. USA 101: 10308 - 10313 (2004).
- Zhang, J., and H. F. Lodish Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 104: 1679 – 1687 (2004).
- Chen, C-Z., L. Li, M. Li, and H. F Lodish The EndoglinPositive Sca-1Positive RhodamineLow phenotype defines a near homogeneous population of long–term repopulating hematopoietic stem cells. Immunity 19: 525 - 533 (2003).
- Ruan, H., H. J. Pownall, and H. F. Lodish. Troglitazone antagonizes TNF-alpha induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-B J. Biol. Chem. 278: 28181 - 28192 (2003).
- Chen, C-Z., L. Li, H. F. Lodish, and D. P. Bartel. MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science (Dec. 4, Epub 2003).
- Ruan, H., N. Hacohen, T. R. Golub, L. Van Parijs and H. F. Lodish Tumor necrosis factor- suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: Nuclear Factor-B activation by TNF-alpha is obligatory. Diabetes. 51: 1319 - 1336 (2002).
- Kratchmarova, I., D. E. Kalume, B. Blagoev, P. E. Scherer, A. V. Podtelejnikov, H. Molina, P. E. Bickel, J. S. Andersen, M. M. Fernandez, J. Bunkenborg, P. Roepstorff, K. Kristiansen, H. F. Lodish, Matthias Mann, and A. Pandey A Proteomic Approach for Identification of Secreted Proteins During the Differentiation of 3T3-L1 preadipocytes to Adipocytes Molecular and Cellular Proteomics 1: 213 - 222 (2002).
- Ruan, H., P. D. G. Miles, C. M. Ladd, K. Ross, T, R. Golub, J. M. Olefsky and H. F. Lodish Profiling Gene Transcription in vivo Reveals Adipose Tissue as an Immediate Target of TNF-alpha: Implications for Insulin Resistance. Diabetes. 51: 3176-3188 (2002).
- Chen, C-Z; M. Li, D. de Graph, S, Monti, B. Göttgens, M.-J. Sanchez, E. S Lander, T. R Golub, A, R. Green, and H. F Lodish Identification of Endoglin as a novel functional marker that defines long-term repopulating hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 99: 15468 - 15473 (2002).
Last Updated: April 9, 2008