Fraydoon Rastinejad

Fraydoon Rastinejad, Ph.D.[Lake Nona in Orlando]

  • Research

    Dr. Rastinejad’s laboratory is interested in the nuclear hormone receptors that regulate metabolic pathways.

  • Biography

    Dr. Rastinejad received his Ph.D. in Biophysics from the University of Pennsylvania, Philadelphia in 1992.

Publications

 

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Fraydoon Rastinejad's Research Focus

Breast Cancer, Cardiovascular Diseases, Atherosclerosis, Heart Disease, Inflammatory/Autoimmune Disease, Metabolic Diseases, Diabetes - General, Metabolic Syndrome

Fraydoon RastinejadWatch Dr. Rastinejad describe his research

Our laboratory studies the family of nuclear hormone receptors that regulate genetic pathways in metabolism. We are examining how these ligand-activated transcription factors physically interact with small molecule ligands, their DNA binding sites and also co-regulatory proteins. Central to our work is the use of protein crystallography / X-ray diffraction and other biophysical approaches that help us visualize the atomic details of how nuclear receptors mediate these complex interactions. There are 48 distinct human nuclear receptors in humans, some having well characterized ligands and functions and others remaining “orphans”, largely uncharacterized in terms of their functions and ligands.


The steroid hormone receptor subgroup, including the estrogen receptor, progesterone receptor, androgen receptor, glucocorticoid receptor as a class, are validated drug targets long exploited for clinical applications. The development of novel synthetic ligands has allowed therapeutic applications in settings ranging from cancer, to fertility, to inflammation. For other nuclear receptors, such as the peroxisome proliferator activated receptors (PPARs), synthetic ligands have found clinical use as insulin sensitizers for type II diabetics.


As we also have a drug-discovery point of view, our goal is to visualize the complete pictures of these nuclear receptor polypeptides in their most functionally revealing complexes. This type of direct visualization can allow us to understand how the various parts of these receptors work together to shape the pharmacological and therapeutic responses to small molecule ligands. A fragment of these receptor polypeptides, known as the ligand binding domain (LBD), has been the primary focus of X-ray diffraction studies up to now. But now, a more thorough understanding of the entire receptor polypeptide, which always consists of multiple domains arranged in tandem, is being pursued in our laboratory. A recent example involved the complete crystal structure determination of PPARgamma in complexes with DNA and different synthetic ligands and coregulator peptides. We are now looking to other members of the nuclear receptor family to examine and understand their physical organization and the way in which they can be exploited for drug discovery and therapeutic potential.


The laboratory is also interested in characterizing the orphan receptors with possible roles in metabolic signaling, including identifying both natural and synthetic ligands that can act as both agonists and antagonists. We recently characterized the Rev-Erb receptor ligands to be iron-porphyrin IX (heme). Free heme levels, whose levels oscillate in some cells under circadian control, allow these receptors tpo control both metabolic regulatory genes and aspects of the cellular peripheral clocks, integrating these two pathways. Other orphan receptors remain to be similarly characterized, not just in terms of their ligands, but also in terms of the complex genetic pathways that they regulate and their disease therapeutic potential as drug targets.

About Fraydoon Rastinejad

Experience

Fraydoon Rastinejad, Ph.D., received B.A degrees in Mathematics and in Biochemistry & Molecular Cell Biology from Northwestern University, Evanston, Illinois, in 1987. His Ph.D. in Biophysics was earned from the University of Pennsylvania, Philadelphia, in 1992. He spent three years at Yale University training in X-ray crystallography with Professor Paul Sigler, before moving onto his first independent faculty career in 1995. Dr. Rastinejad has served as faculty at the University of Virginia School of Medicine beginning December 1995 through June 2010, where he was last appointed joint Professor of Pharmacology and Biochemistry & Molecular Genetics, and also director of the Center of Molecular Design. His current research interests, as Professor at Sanford-Burnham, involve integrating structural studies with development of small-molecule tools and cell-based characterizations of nuclear receptor pathways. In addition to the nuclear receptor arena, Dr. Rastinejad’s laboratory has elucidated a number of structures and mechanisms related to histone tail modifications and their recognition factors.

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