IOTF Fellowship Program # 3 and 4

Mentor:
Akhilesh K. Nagaich, Ph.D

Organizational Affiliation and Position:
Senior Staff Fellow
Laboratory of Chemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, FDA

Contact Information:
akhilesh.nagaich@fda.hhs.gov (301) 827-1780

Running Title of Research Program:
Epigenetic Mechanisms in Cancer Development

Project Summary:
Epigenetic mechanisms play a central role in the genesis of most, if not all cancers. Several recent studies have implicated aberrant chromatin remodeling activity in the development of human cancer. Evidence has emerged that perturbation of complexes that remodel chromatin by mobilizing nucleosomes may have a central role in tumor suppression and oncogenic transformation. Our lab is investigating mechanism of action of ATP dependent chromatin remodeling enzymes and how they cooperate with p53 and steroid nuclear receptors to prevent oncogenic transformation.

Proposed Project for the Fellow:
The fellow will have the opportunity to pursue one of several projects to study mechanism of action of chromatin remodeling enzymes and their role in genome function. Exciting projects include studies on (i) the role of ATP-dependent chromatin remodeling complexes in p53-mediated transcriptional regulation; (ii) the enzymology of ATP-dependent chromatin remodeling proteins, and (iii) the role of chromatin architectural proteins in transcription and higher order chromatin organization. The laboratory is located on the main NIH campus in Bethesda and has access to excellent core facilities and the NIH library.

Regulatory Activity:
The fellow will perform regulatory review of therapeutic enzymes and other oncology products as part of an inter-disciplinary team to assess the potential efficacy and safety of the drugs, and communicate directly with product sponsors.

References:
Barrett HH, Myers KJ. Foundations of Image Science, John Wiley & Sons, Inc., New York, 2004.

Akhilesh K. Nagaich, Dawn Walker, Ron Wolford and Gordon L. Hager "Rapid Periodic Binding and Displacement of the Glucocorticoid Receptor during Chromatin Remodeling" (2004) Molecular Cell, 14,163-174

Akhilesh K. Nagaich and Gordon Hager "Chromatin Remodeling and Transcription Factor accessibility using UV Laser Crosslinking: A Real Time Assay" (2004) Science STKE, 256, pl13

Akhilesh K. Nagaich, Victor Zhurkin, S. R. Durell, R.L. Jernigan, E. Appella and R. E. Harrington " p53-induced DNA bending and twisting: p53 tetramer binds on the outer side of a DNA loop and increases DNA twisting (1999)" Proc. Natl. Acad. Sci, 96, 1875-80, USA