Marianne A. Grant, Ph.D.
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-270E
Boston, MA 02215
Dr. Marianne A. Grant is an Assistant Professor of Medicine at Harvard Medical School (HMS) and in the Division of Cardiovascular Medicine at Beth Israel Deaconess Medical Center (BIDMC). Dr. Grant received her PhD from Brown University in the Pharmacology, Biotechnology and Physiology Department where she was awarded a pre-doctoral fellowship from the PhRMA Foundation to study neuromuscular and neuronal ion channel structure-function using nuclear magnetic resonance NMR spectroscopy. Dr. Grant did her postdoctoral research to study the structure and function of pro- and anticoagulant proteins in the Division of Hemostasis and Thrombosis at the BIDMC with Dr. Alan Rigby where she earned an NIH NRSA F32 Fellowship for her postdoctoral studies. In 2006 Dr. Grant was recruited to the Division of Molecular and Vascular Medicine at BIDMC and became a member of the Center for Vascular Biology Research (CVBR). She received an American Heart Association Scientist Development grant in 2008, and within a time thereafter established a protein structure and drug discovery research program in cardiovascular medicine focused primarily on transcription factor biology that is supported by the NIH National Heart, Lung, and Blood Institute (NHLBI).
Research Interests: Protein Structure-Biomolecular Recognition-Computational Biology-Drug Discovery
Basic Research - My laboratory investigates the three dimensional structure, function, and interactions of proteins at the atomic level. Our aim is to apply the tools of structural biology to an understanding of molecular structure-function, particularly for macromolecules that are targets for therapeutic intervention in human disease. We use of a combination of molecular, biochemical, and biophysical techniques in our work. In particular, we use nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to determine the structures of proteins and complexes that are therapeutic targets in human disease. We use computational analysis to investigate protein structure-function relationships and examine the molecular docking between proteins and small molecule drugs. We also use computer simulations to analyze the molecular interactions between proteins to discover novel allosteric mechanisms to regulate/modulate the activities of therapeutic targets.
Topics we are currently investigating include i.) gene regulation (transcriptional activity and regulation) in the vascular endothelium, and ii.) molecular pathways of growth inhibition and apoptosis.
Gene Regulation in the Vascular Endothelium. We are investigating molecular mechanisms of gene regulation important in human vascular systems, with an emphasis on gene expression that regulates vascular endothelial cell growth control and angiogenesis or is extremely important in cardiac physiology. Our goal is to understand the regulation of genes critical for new vessel growth, as well as genes that modulate cardiovascular biology. Toward this end, the fundamental aspects of protein structure, molecular recognition, and conformational alteration in protein transcription factor families are currently under investigation. In addition, we are interested in studying the interactions between transcription factors that synergistically control gene expression and are implicated in human vascular dysfunctions, including cardiovascular disease and diabetes.
Molecular pathways of growth inhibition and apoptosis. We are investigating the structure-function of proteins playing critical roles in cell growth inhibition and cell apoptosis. In particular, these proteins function as adhesives or adaptors in multimeric protein complexes crucial to signal transduction pathways and protein translocation mechanisms that are important in cell growth control. Our aim is to advance our molecular understanding of these proteins and their interactions and to elucidate novel mechanisms to therapeutically interrogate their function and complex formation.
New and Noteworthy Publications:
Li, Y, Bourbon, PM, Grant, MA, Peng, J, Ye, T, Zhao, D, Zeng, H. (2015) Requirement of novel amino acid fragments of orphan nuclear receptor TR3/Nur77 for its functions in angiogenesis, Oncotarget, 6(27): 24261-76. This study shows that TR3 is an excellent target for pro-angiogenesis and anti-angiogenesis therapies. These studies further our understanding of the molecular mechanism by which TR3 regulates angiogenesis and set the foundation for the development of high-throughput screening assays to identify compounds targeting TR3 for pro-angiogenesis and anti-angiogenesis therapies.
Dharaneeswaran, H, Abid, R, Yuan, L, Dupuis, D, Beeler, D, Spokes, KC, Janes, L, Sciuto, T, Kang, P, Jaminet, S-C, Dvorak, AM, Grant, MA, Regan, ER, Aird, WC . (2014) FoxO1-mediated activation of Akt plays a critical role in vascular homeostasis, Circ. Res, 115(2):238-51. This study uses several genetic mouse models to address the role of endothelial FOXO1 in homeostasis and provides evidence that endothelial FOXO1 is both necessary and sufficient for viability, and that a balanced level of FOXO1 activity is required for survival. Moreover, we show that a primary role of FOXO1 in the endothelium is to feed back and activate Akt-mTORC1, to sensitize cells to the effect of VEGF.
Choy, WC, Datta, D, Geiger, CA, Birrane, G, and Grant, MA. (2013) Crystallization and preliminary X-ray analysis of a complex of the FOXO1 and ETS1 DNA-binding domains and DNA, Acta Crystallogr, 70: 44-48. This study reports crystallized DNA-binding domains of Ets1 and FOXO1 transcription factors in complex with the FOX:ETS DNA sequence. The ternary structure provides a first understanding of how FOX and ETS synergistically mediate endothelial-specific transcriptional activity in the vasculature and insight into the cooperative regulation of gene expression in adult neovascularization and vascular homeostasis.
Grant, MA . (2011) Integrating computational protein function prediction into drug discovery initiatives. Drug Develop Res, 72(1): 4-16. This article surveys current bioinformatic programs and approaches for protein function prediction/annotation and discusses their integration into drug discovery initiatives. The development of such methods to annotate protein functional sites and their application to large protein functional families is crucial to successfully utilizing the vast amounts of genomic sequence information available to drug discovery and development processes.
Grant, MA, Baron, RM, Macias, AV, Perrella, MA, Rigby, AC. (2009) Netropsin improves survival from endotoxemia by disrupting HMGA1-binding to the NOS2 promoter, Biochem J., 418(1):103-112. This study elucidates through biophysical and structural data the beneficial effect of netropsin on survival outcomes in a septic shock model through interference with HMGA transcription factor binding in the NOS2 promoter.
Grant, MA. (2009) Protein structure prediction in structure-based ligand design and virtual screening. Comb Chem High Throughput Screen, 12(10):940-60. This article describes method advancements in protein structure prediction and assesses the application of predicted protein structures to structure-based ligand design.