This proposal focuses on the development of a new therapeutic for systemic lupus erythematosus. The overall goal is to 1) modify a peptide mimetope of DNA to increase serum half life, permit oral administration, and maximize function, 2) to explore the functionality of two new compounds with similar binding properties to the peptide and 3) develop additional compounds. The mimetope binds to a subset of anti-DNA antibodies that deposit in glomeruli, cross-react with NMDA receptors and mediate excitotoxic neuron death, and, in immune complexes, activate dendritic cells. Efforts will be made to use radioisotope-tagged peptide/modified compound to ablate antigen-specific B cells. It will also be determined if peptide intercalates into DNA-containing immune complexes to diminish activation of dendritic cells. Finally, new peptide mimetopes of DNA will be sought in case more than one subset of anti-DNA antibodies or DNA-reactive B cells must be eliminated to reduce disease pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057084-05
Application #
8654295
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$351,389
Indirect Cost
$139,709
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Son, Myoungsun; Diamond, Betty (2014) C1q-mediated repression of human monocytes is regulated by leukocyte-associated Ig-like receptor 1 (LAIR-1). Mol Med 20:559-68
Bloom, Ona; Cheng, Kai Fan; Cheng, Kai Fen et al. (2011) Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc Natl Acad Sci U S A 108:10255-9