Proper regulation of innate and adaptive immune responses is critical for the maintenance of homeostasis in intestinal tissues and in bringing an immune response to closure in order to restore balance once the requirement for inflammation is ended and repair required such as in inflammatory bowel disease (IBD). This research proposal addresses the unanswered question of how carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is regulated and in turn regulates intestinal immune responses. Our long-term go`al is to understand how his knowledge can be utilized in the treatment of IBD. The objective of this research is to understand how CEACAM1 isoform expression through alternate splicing is regulated in mucosal tissues, how these isoforms function in the maintenance of homeostasis or regulation of inflammation and the specific intracellular signaling pathways involved. The central hypothesis is that the level and types of CEACAM1 isoforms are directly controlled by the commensal microbiota and that the signaling from these isoforms are associated with distinct functional outcomes that have the common property of maintaining homeostasis through either direct inhibition of immune receptor signaling (CEACAM1-L) or indirect regulation of mucosal lymphocyte function via the induction of unique types of regulatory pathways (e.g. CD4+LAP+ T cells) or processes (e.g. IgA production). The rationale is derived from the emerging view that the relative expression of CEACAM1-long (L) and -short (S) isoforms in a T cell resolves into a tunable system that regulates the overall functional properties of a T cell. Guided by extensive preliminary data, the central hypothesis will be tested in three specific aims: 1) Determine how CEACAM1 expression is regulated in mucosal tissues;2) Define the physiologic functions of CEACAM1 in influencing homeostasis versus inflammation in mucosal tissues, and;3) Elucidate the mechanism(s) of CEACAM1-S signaling and its regulation by CEACAM1-L.
In Aim 1, we seek to understand the mechanism(s) by which commensal microbiota and tolerogenic signals (T cell receptor/CD3 complex signaling) regulate CEACAM1 expression, splicing and responses to antigen.
In Aim 2, using newly created Ceacam1-/- mice and mice with conditional transgenic expression of specific types of CEACAM1- isoforms in T cells, we seek to understand the mechanisms by which CEACAM1 regulates homeostasis.
In Aim 3, we will determine the specific intracellular pathway of CEACAM1-S signaling and define how this is regulated by CEACAM1-L isoforms and the potential for targeted induction of regulatory T cells. Overall, this proposal will gain insights into the fundamental mechanisms of CEACAM1 function, which is significant because it will elucidate CEACAM1 regulation by indigenous environmental factors and the manner in which this regulation results in the maintenance of mucosal homeostasis and the control of intestinal inflammation and other pathologic processes. Such knowledge is expected to identify new strategies for targeting the immune system in the goal of inhibiting inflammation or enhancing anti-tumor and anti-infective immunity.
The proposed research is relevant to public health because understanding how CEACAM1 expression is regulated by commensal microbiota and in turn linked to the control of functional pathways associated with T cells such as regulation and secretory immunity will provide new insights into the mechanisms that maintain mucosal homeostasis. The proposed studies are relevant to the mission of the NIDDK because they are expected to identify new therapeutic strategies for inhibiting inflammation associated with inflammatory bowel disease or enhancing immunity in the treatment of cancers and infections.
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