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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Hamilton, Frank A
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Brigham and Women's Hospital
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