Restricted Research - Award List, Note/Discussion Page

Fiscal Year: 2014

2048  The University of Texas at San Antonio  (23608)

Principal Investigator: Cardona, Astrid

Total Amount of Contract, Award, or Gift (Annual before 2011): $ 264,600

Exceeds $250,000 (Is it flagged?): Yes

Start and End Dates: 2/3/12 <> 11/30/16

Restricted Research: YES

Academic Discipline: STCEID-PI-CARDONA ASTRID E  

Department, Center, School, or Institute: South Texas Center for Emerging Infectious Diseases (STCEID)  Center for Research and Training in the Sciences (CRTS)  

Title of Contract, Award, or Gift: Role of CX3CR1 in adaptive immunity during autoimmune encephalomyelitis

Name of Granting or Contracting Agency/Entity: National Institutes of Health

Program Title: none
CFDA Linked: Biomedical Research and Research Training


The transmembrane chemokine fractalkine (CX3CL1) present on neurons and peripheral endothelial cells acts as an adhesion molecule or as a soluble chemoattract. CX3CL1 signals through its receptor CX3CR1 which is expressed in microglia, monocytes/macrophages and dendritic cells, NK cells and T cells. Notably, multiple sclerosis patients revealed lower expression of CX3CR1 in peripheral NK cells when compared to healthy controls1 and lack of CX3CR1+ cells in peripheral blood correlated with disease activity. However, the role of CX3CR1 in antigen presenting cells and T cells, and their contribution to CNS pathology are still enigmatic. The hypothesis behind the proposed research is that CX3CR1/CX3CL1 regulates antigen presenting cell (APC) effector functions influencing the development of pathogenic T cells during experimental autoimmune encephalomyelitis (EAE). This hypothesis is based on the following: 1) Worse EAE symptoms and enhanced demyelination were observed in CX3CR1-deficient mice, 2) absence of CX3CR1 correlated with a selective accumulation of CD115+CD11c+ dendritic cells to CNS tissues, and 3) Bone marrow chimeric mice revealed that absence of CX3CR1 in bone marrow induced an unusual, severe and chronic non-remitting EAE disease with sustained paralysis. The overall goal of this proposal is to elucidate the function of CX3CR1 during EAE and how it regulates pathogenic CNS inflammation. The specific aims are: 1. To determine the role of CX3CR1 in initiation of disease at the level of antigen presentation and T cell priming. We will test the hypothesis that CX3CR1 controls peripherally DC maturation affecting antigen presentation and subsequently peripheral T cell polarization. We will investigate the role of CX3CR1 antigen trafficking and dendritic cell mobilization and effects of CX3CR1-deficiency in generation of encephalitogenic T cells. 2. To determine the role of CNS and peripheral CX3CR1 deficiency in the effector phase of EAE and their contribution to neuronal damage and demyelination. We hypothesize that absence of CX3CR1 in bone marrow is critical for the maintenance of T cell mediated inflammation and tissue damage in the EAE brain. We will investigate the role of CX3CR1 in inhibitory signaling, and in activation, and survival of pathogenic and regulatory T cell subsets within CNS tissues at peak of disease and at time of recovery. 3. To evaluate the role of cells expressing the human CX3CR1I249/M280 or CX3CR1V249/T280 receptor during EAE. We hypothesize that I249/M280 expressing cells will exhibit effector functions comparable to CX3CR1-deficient cells during CNS autoimmunity. We will use knock-in mice expressing the human variant as a low affinity model to investigate the role of the I249/M280 in APC activation and T cell polarization in vivo.

Discussion: No discussion notes


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