CDId is a major histocompatibility complex (MHC) class 1-related molecule that is expressed by intestinal epithelial cells (lEC), hepatocytes and professional antigen presenting cejls (APCs) including dendritic cells (DC), monocytes and B cells. CDId functions in the presentation of the hosit and microbialy derived lipid antigens to CDId-restricted T ceils that express natural killer (NK) and T cell markers (sd-called NKT cells). CDId-restricted antigen presentation is operational during the eariiest phases of an immune response, which, together with the broad array of cytokines secreted by activated NKT cells, accounts for the wide range of effects that CDId-restricted presentation has on immune-mediated processes in vivo. Although the cell biology of the host (and microbial) lipid antigen acquisition by CDId or the role of CDId-restricted Antigen presentation pathways in mucosal tissues is poorly understood, CDId-restricted pathways;are now| known to regulate inflammation and host defense in the intestines and liver. We propose to examine the riecently appreciated relationship between microsomal triglyceride transfer protein (MTP), an endbplaismic reticulum (ER) resident protein, which possesses a well-known role in lipid absorption mediated through the lipidation of apolipoprotein-B in the liver and intestine, and the ihrimune functions of CDId.
Aimi l investigates the hypothesis that MTP is responsible for the lipidation and assembly of CDId and seeks;to prove that MTP lipidates CDId, to define the location within CDId biogenesis that MTP functions relative to other ER chaperones, to determine whether MTP has distinct lipidation and chaperone functions forCDId and to define the cellular locale of CDId when MTP is absent.
Aim 2 proposes to determine whether MTP is expressed by and is functional in professional APCs such as DCs and B cells, to determine whether:MTP affects CDId trafficking behavior in professional APCs and establish an irj vivo model for MTP deficiency in hemotopoietic cells.
Aim 3 proposes to use mice with conditional deletion of MTP in lECs to define the role of these pathways in the developmerit of colitis due abnormal barrier function and the specific role that t)ie lEC and CDIdrestricted antigen presentation plays in the developrnent of colitis.
Aim 4 proposes to define the role of CDId in regulating intestinal colonization with commensal bacteria and determine if MTP;regulates bacterial colonization of the intestine and define the APC involved.

Public Health Relevance

Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident protein that has recently been appreciated to provide the nascent lipid(s) for GDI assembly during its biogenesjs in addition to its previously recognized role in lipid absorption during digestion. Given the role of CDId in participating in a wide variety of immune-mediated diseases, understanding the mechanisms of MTP-mediated lipidation of CD1 and its functional consequences is extremely important. Such studies wjll form the basis for the possibility of specifically inhibiting CD1 at its eariiest stages of assembly within the SR and thus provide opportunities for controlling inappropriate inflammatoiy responses or enabling others th$t may normally be inhibited by GDI-mediated pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK044319-22
Application #
8663220
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hamilton, Frank A
Project Start
1992-09-30
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
22
Fiscal Year
2014
Total Cost
$759,212
Indirect Cost
$258,426
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Krishnamoorthy, Sriram; Liu, Tongyao; Drager, Douglas et al. (2016) Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice. Cell Immunol 301:30-9
Arabzadeh, Azadeh; Dupaul-Chicoine, Jeremy; Breton, Valérie et al. (2016) Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells. Gut 65:821-9
Gensollen, Thomas; Iyer, Shankar S; Kasper, Dennis L et al. (2016) How colonization by microbiota in early life shapes the immune system. Science 352:539-44
Nakanishi, Yuki; Reina-Campos, Miguel; Nakanishi, Naoko et al. (2016) Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι. Cell Rep 16:3297-310
Hosomi, Shuhei; Kaser, Arthur; Blumberg, Richard S (2015) Role of endoplasmic reticulum stress and autophagy as interlinking pathways in the pathogenesis of inflammatory bowel disease. Curr Opin Gastroenterol 31:81-8
Zeissig, Sebastian; Petersen, Britt-Sabina; Tomczak, Michal et al. (2015) Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut 64:1889-97
Pyzik, Michal; Rath, Timo; Lencer, Wayne I et al. (2015) FcRn: The Architect Behind the Immune and Nonimmune Functions of IgG and Albumin. J Immunol 194:4595-603
Rath, Timo; Baker, Kristi; Dumont, Jennifer A et al. (2015) Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol 35:235-54
Dowds, C Marie; Blumberg, Richard S; Zeissig, Sebastian (2015) Control of intestinal homeostasis through crosstalk between natural killer T cells and the intestinal microbiota. Clin Immunol 159:128-33
Huang, Yu-Hwa; Zhu, Chen; Kondo, Yasuyuki et al. (2015) CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517:386-90

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