The TIM family of genes consists of eight members {TIM-1-8) on mouse chromosome 11B1.1, and three members {Tlf /I1, TIMS, and TIM4) on human chromosome 5q33.2 (5). All ofthe mouse and human TIM genes encode type 1 membrane proteins, consisting of an N-terminal Cys-rich IgV-like domain, a mucin-like domain, a transmembrane domain, and an intracellular tail (Figure 1). The intracellular tails of TIM-1, TIM-2, and TIM-3, but not TIM-4, contain predicted tyrosine phosphorylation motifs, suggesting that these TIMs are involved in transmembrane signaling. Whereas TIM-3 has only three predicted glycosylation sites, human TIM-1 has 60, which are primarily 0-linked glycosylation motifs located within the mucin-like domain. The N-terminal Cys-rich regions ofthe TIM homologs have a sequence identity of about 40%, whereas sequence identity between the mouse and human orthologs is around 60% (6). The structural similarities between all the TIMs suggest that they arose from an ancestral gene by successive gene duplication events. TIM-1 polymorphisms and protection against asthma and allergy. Human TIM-1 (HUGO designation HAVCR1) is highly polymorphic in humans and monkeys, as it is in mice, with single nucleotide polymorphisms (SNPs) as well as insertion/deletion variants occurring primarily in the mucin-like domain in both mice and humans (as defined in the previous Project 1). We have also performed association analysis ofthe insertion/deletion variants of TIM-1 in

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI054456-09
Application #
8667719
Study Section
Special Emphasis Panel (ZAI1-RRS-I (M2))
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$226,742
Indirect Cost
$63,323
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Kim, Hye Young; Umetsu, Dale T; Dekruyff, Rosemarie H (2016) Innate lymphoid cells in asthma: Will they take your breath away? Eur J Immunol 46:795-806
Brauner, Eran; Gunda, Viswanath; Vanden Borre, Pierre et al. (2016) Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer. Oncotarget 7:17194-211
Mahoney, Kathleen M; Rennert, Paul D; Freeman, Gordon J (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561-84
Mahoney, Kathleen M; Freeman, Gordon J; McDermott, David F (2015) The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther 37:764-82
Echbarthi, Meriem; Zonca, Manuela; Mellwig, Rachel et al. (2015) Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse. Traffic 16:1193-207
Kroy, Daniela C; Ciuffreda, Donatella; Cooperrider, Jennifer H et al. (2014) Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 146:550-61
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59
Recacha, Rosario; Jiménez, David; Tian, Li et al. (2014) Crystal structures of an ICAM-5 ectodomain fragment show electrostatic-based homophilic adhesions. Acta Crystallogr D Biol Crystallogr 70:1934-43
Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara et al. (2014) TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 40:542-53

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