Site Visit Update: Division of Therapeutic Proteins. Amy Rosenberg, MD, Director. Amy Rosenberg, MD, Director Barry Cherney, Ph.D, Deputy Director Sandra Chung, Secretary. Laboratory of Biochemistry Emily Shacter, Ph.D., Chief Jee Chung, Ph.D., IOTF Fellow Hiroshi Uehara, Ph.D., Biollgist.
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Amy Rosenberg, MD,
Barry Cherney, Ph.D, Deputy Director
Sandra Chung, Secretary
Laboratory of Biochemistry
Emily Shacter, Ph.D., Chief
Jee Chung, Ph.D., IOTF Fellow
Hiroshi Uehara, Ph.D., Biollgist
Laboratory of Chemistry
Gibbes Johnson, Ph.D., Chief
Y-X Fan, Ph.D., Visiting Associate
N. Spiridinov, Ph.D., Visiting Associate
Lily Wong, Microbiologist
Laboratory of Immunology
Elizabeth Shores, Ph.D., Chief
Baolin Zhang, Ph.D., Senior Staff Fellow
Yaqin Zhang, MD
Serge Beaucage, Ph.D., PI
A Grajkowski, Ph.D., Visit Associate
J. Cieslak, Ph.D., Visit Associate
Michael Norcross, MD PI
Jinhai Wang,MD Staff Scientist
Gregory Rodriquez, Microbiologist
Akhilesh Nagaich, Ph.D., Senior Staff Fellow
Amy Rosenberg, MD PI
Hugh McFarland, Ph.D, Staff Scientist
Lai Xu, Ph.D., MD, Staff Fellow
Karen Mason, Bio Lab Tech
Full Time Review Staff
Ingrid Markovic, Ph.D.
Dov Pluznik, Ph.D..
Kathy Lee, MS
Full Time Review Staff.
Wei Guo, Ph.D.
Kurt Stromberg, MD
Emmanuela Lacana, Ph.D.
Daniela Verthelyi, Ph.D., MD.
Senior Staff Fellow
J. Pedras-Vasconcelos, Visiting Associate
M. Puig, Visiting Associate
Vivian Wang, Microbiologist
Raymond Donnelly, Ph.D., PI
H. Dickensheets, Ph.D., Staff Scientist
Faruk Sheikh, Ph.D. Visiting Associate
Full Time Review Staff
Susan Kirshner, Ph.D
Ennan Guan, Ph.D., MD
.The Division of Therapeutic Proteins
and IND products in DTP
Immunology and Autoimmunity
Regulation of chemokine products: potency assays, mechanism of action
Regulation of protein therapeutics for HIV-1 treatment and prevention
Cytokines and interferons for treatment and immune reconstitution
Chemokine receptor inhibitors
Regulation of protein therapeutics for treatment of malignant states
Evaluation of immunogenicity of therapeutic protein products; TNF inhibitor productsResearch Program of Michael Norcross, MD
Chemokines and Chemokine Receptors in HIV-1 infection and Immunology:
Heterodimeric interactions between different types of chemokines and receptors have been studied. Expression vectors are being generated to dissect the interactions between CCR5, CXCR4, CD4 and CD26 using FRET techniques. Physical interactions between these cell surface proteins may control susceptibility to infection and sensitivity to receptor ligands and antagonists.
Wang, J, Guan, E, and Norcross, MA. Heterodimer formation between CC and CXC chemokines (Manuscript in preparation)
Immune modulation and HIV-1 pathogenesis:
Studies are ongoing to examine the effects of HIV infection and HIV proteins on macrophage and dendritic cell function. HIV infection was found to induce partial dendritic cell activation that may contribute to chronic immune activation seen in HIV infected patients. Specific inhibitors of TLR receptors and scavenger receptors are being evaluated for effects on HIV mediated activation of monocytes and dendritic cells.
Projects on going
------Receptor, trafficking, and regulation of monocyte functions by pDCs.
Rhodamine-labeled rODNs were taken up by monocytes within minutes w/o pDC (Confocal). Labeled rODN entry into monocytes was not inhibited by anti-CXCL16 (Confocal & FACS). rODN was colocalized with lysosome marker within one hour (Confocal). rODNs induced FSC and SSC changes and prolonged the survival of monocytes significantly.
------CXCR4, cancer factor, migration, and function of immune cells: a soluble factor secreted by breast cancer cells upregulated HLA-DR, downmodulated CXCR4on monocytes, blocked by anti-GM-CSF.
Class switch recombination
IgH Insulators: prediction, prevention, control of immune responses
Immunogenicity of protein therapeutics review
Immunomodulatory product review
products to activate B cells in setting of immune deficiency
product qualities associated with Tind and Tdep B cell activation, ie aggregates
Evaluation of biotech applications using insulators to stabilize and enhance transgene expression; replacement of defective genes, prevention of oncogene activation.Research Program of Edward Max, Ph.D., MD
Class Switch Recombination project (Arudchandran, Bernstein):
Additional experiments completed to compare double- and single-strand DNA breaks in Ig Switch regions; only double stranded breaks are AID-dependent.
Manuscript submitted to J Exp. Med. “Single-strand DNA breaks in immunoglobulin Class Switch Recombination that depend on UNG but not AID”
ChIP experiments to assess APOBEC3 binding to Ig Switch regions; RTPCR for APOBEC3 expression in B cells
IgH Insulator project (Bernstein, Mills):
In vitro binding of candidate regulatory proteins USF1 and DB1 to insulator DNA has been characterized
Barrier activity flanking insulator further mapped
Manuscript draft: “A chromatin boundary element downstream of the human immunoglobulin heavy chain locus.”
IgH Insulator project:
Optimization of methods for production of diagnostic and therapeutic oligonucleotides
Expertise in Chemistry
Co-author Oligonucleotide guidance document;
Review of therapeutic oligonucleotides, siRNA INDs
Review of BLA-PCR Based Diagnostic (CBER)
Regulation of pegylated products: reaction kinetics, stability
Regulation of therapeutic enzymes: enzyme activity, stability.Serge Beaucage, Ph.D., Progress Update
1. Grajkowski, A., Cieślak, J., and Beaucage, S. L. Functionalization of Long Chain Alkylamine Controlled-Pore Glass for Thermolytic Release of DNA Oligonucleotides and Their Conjugates. To besubmitted for publication in Bioconjugate Chemistry.
2. Ausín, C. and Beaucage, S. L. Synthesis of Deoxyribonucleoside Phosphoramidites Functionalized with Lipophilic and Hydrophobic Groups at P(III) for Incorporation into CpG-Oligonucleotide Produgs. To besubmitted for publication in the Journal of Organic Chemistry.
3. Cieślak, J., Grajkowski, A., and Beaucage, S. L. The 4-(N-dichloroacetyl-N-methylaminobenzyloxy)methyl group for 2’-Hydroxyl protection in the Solid-Phase Synthesis of Oligoribonucleotides. To besubmitted for publication in the Journal of Organic Chemistry.
4. Beaucage, S. L. Solid-Phase Synthesis of siRNA Oligonucleotides. To besubmitted for publication in Current Opinion in Drug Discovery & Development.