C1 inhibitor (C1INH) is a serine proteinase inhibitor that regulates activation of the classical complement pathway and the contact system of kinin generation. Normal regulation of C1INH appears to depend upon responsiveness to interferons (IFN), IL-6 and possibly to corticosterioids and androgens. The investigator proposes to characterize the TATA-less initiator driven C1INH promoter using reporter constructs, electrophoretic mobility shift and DNase I footprinting assays with site directed mutagenesis to define the required elements. The characterization of the IFN-stimulated response elements (ISRE) in the first intron and the upstream INF-gamma activation sequences (GAS) will be completed, and their relative roles in regulation of C1INH by IFN-alpha and IFN-gamma will be defined. The function of the putative androgen/ glucocorticoid and IL-6 responsive elements will be defined, as will the hypothesized interaction between nuclear factor IL-6 and the androgen/ glucocorticoid receptors. One mutant C1INH has been described that appears to inhibit translation of the normal wild type transcript. The mechanism of this inhibition will be determined. This observation may have important implications for regulation of synthesis in other diseases that develop in heterozygous deficiency states and for normal regulation of synthesis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD033727-05
Application #
6128977
Study Section
Special Emphasis Panel (ZRG5-IMS (01))
Program Officer
Lock, Allan
Project Start
1996-02-01
Project End
2000-07-31
Budget Start
1999-05-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
Davis 3rd, Alvin E (2006) Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am 26:633-51
Liu, Dongxu; Zhang, Dong; Scafidi, Jennifer et al. (2005) C1 inhibitor prevents Gram-negative bacterial lipopolysaccharide-induced vascular permeability. Blood 105:2350-5
Liu, Dongxu; Cramer, Cort C; Scafidi, Jennifer et al. (2005) N-linked glycosylation at Asn3 and the positively charged residues within the amino-terminal domain of the c1 inhibitor are required for interaction of the C1 Inhibitor with Salmonella enterica serovar typhimurium lipopolysaccharide and lipid A. Infect Immun 73:4478-87
Cai, Shenghe; Dole, Vandana S; Bergmeier, Wolfgang et al. (2005) A direct role for C1 inhibitor in regulation of leukocyte adhesion. J Immunol 174:6462-6
Liu, Dongxu; Gu, Xiaogang; Scafidi, Jennifer et al. (2004) N-linked glycosylation is required for c1 inhibitor-mediated protection from endotoxin shock in mice. Infect Immun 72:1946-55
Cai, Shenghe; Davis 3rd, Alvin E (2003) Complement regulatory protein C1 inhibitor binds to selectins and interferes with endothelial-leukocyte adhesion. J Immunol 171:4786-91
Liu, Dongxu; Cai, Shenghe; Gu, Xiaogang et al. (2003) C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide. J Immunol 171:2594-601
Han, Eun D; MacFarlane, Ryan C; Mulligan, Aideen N et al. (2002) Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 109:1057-63
Zahedi, Kamyar; Prada, Anne E; Mulligan, Aideen et al. (2002) Normal transcription of the C1 inhibitor gene is dependent upon a polypurine-polypyrimidine region within the promoter. Inflammation 26:183-91
Zahedi, R; MacFarlane, R C; Wisnieski, J J et al. (2001) C1 inhibitor: analysis of the role of amino acid residues within the reactive center loop in target protease recognition. J Immunol 167:1500-6

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