The laboratory focuses on two areas. The first concerns the properties and function of IA-2 and IA-2 which are major autoantigens in type 1 diabetes and transmembrane proteins of dense core secretory vesicles. These proteins are present in most of the neuroendocrine cells in the body. Knockout and knock down technology has shown that these proteins affect the secretion of hormones (e.g., insulin) and neurotransmitters. Current studies are concerned with the effect of IA-2 and IA-2beta on the secretion of these hormones and neurotransmitters and how they affect a variety of physiologic processes. In addition, the role of micro RNA's in the expressionof the genes encoding these proteins is being examined. The second area concerns polyreactive antibodies. Hybridoma technology has shown that many antibody molecules are polyreactive that is, they can bind to a variety of different and structurally unrelated self and non-self foreign antigens. These antibodies generally have low binding affinity and are encoded by germ-line or near germ-line sequences. Further studies revealed that much of the natural antibody repertoire is made up of polyreactive antibody. The function of the natural antibody repertoire has remained an enigma. Current studies are focusing on the role of polyreactive antibodies in: defense against foreign organisms (i.e., bacteria/viruses);the clearance of damaged proteins and cells (apoptosis)and the possible role of these antibodies in the induction and/or maintenance of immunological tolerance. The cells that make polyreactive antibodies also are under investigation.

Project Start
Project End
Budget Start
Budget End
Support Year
28
Fiscal Year
2013
Total Cost
$1,505,480
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
City
State
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Abuhatzira, Liron; Xu, Huanyu; Tahhan, Georges et al. (2015) Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2β, and GAD65. FASEB J :
Xu, Huanyu; Abuhatzira, Liron; Carmona, Gilberto N et al. (2015) The Ia-2β intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice. Diabetologia 58:2298-306
Sun, Clare; Tian, Xin; Lee, Yuh Shan et al. (2015) Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood :
Shomorony, A; Pfeifer, C R; Aronova, M A et al. (2015) Combining quantitative 2D and 3D image analysis in the serial block face SEM: application to secretory organelles of pancreatic islet cells. J Microsc 259:155-64
Gunti, Sreenivasulu; Notkins, Abner Louis (2015) Polyreactive Antibodies: Function and Quantification. J Infect Dis 212 Suppl 1:S42-6
Qiu, Qi; Xu, Zhili; Tian, Jie et al. (2015) Impact of natural IgM concentration on gene therapy with adenovirus type 5 vectors. J Virol 89:3412-6
Burbelo, Peter D; Lebovitz, Evan E; Notkins, Abner L (2015) Luciferase immunoprecipitation systems for measuring antibodies in autoimmune and infectious diseases. Transl Res 165:325-35
Pfeifer, C R; Shomorony, A; Aronova, M A et al. (2015) Quantitative analysis of mouse pancreatic islet architecture by serial block-face SEM. J Struct Biol 189:44-52
Cai, Tao; Hirai, Hiroki; Xu, Huanyu et al. (2015) The minimal promoter region of the dense-core vesicle protein IA-2: transcriptional regulation by CREB. Acta Diabetol 52:573-80
Cai, Tao; Notkins, Abner L (2015) Pathophysiologic changes in IA-2/IA-2β null mice are secondary to alterations in the secretion of hormones and neurotransmitters. Acta Diabetol :

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