(Applicant?s Abstract) The IgE/FceRI network is central to allergic inflammation and as such may be involved in the genesis of bronchial hyperresponsiveness and asthma. The level of FceRI surface expression is controlled by the level of circulating IgE. This regulation has great physiological significance since increased FceRI expression translates into enhanced effector function. Furthermore, recent anti-IgE clinical trails have underscored the importance of this regulation, showing decreased basophil effector function with corresponding decreased FceRI expression. However, nothing is known of how IgE regulates FceRI expression. We propose to further the understanding of IgE-mediated FceRI regulation through the four following aims.
Specific Aim 1 : Characterize the process of IgE-mediated FceRI up-regulation. In this aim we will dissect the process of IgE-mediated up-regulation of FceRI, determining the mechanism(s) involved.
Specific Aim 2 : Elucidate the impact of classical beta on IgE-mediated up-regulation of FceRL In this aim, we will follow-up on our preliminary data that show IgE-mediated up-regulation of FceRI is significantly greater in alphagamma2 than in alpha beta gamma2 expressing cells in vitro. We will determine the molecular mechanism(s) that underlie this difference. We will also analyze the physiolgical significance of alphagamma2 vs. alphabetagamma2 up-regulation in mice. Finally, we will determine whether known polymorphisms in the beta gene have an impact on IgE-mediated FceRI up-regulation.
Specific Aim 3 : Elucidate the impact of a new product of the beta gene on IgE-mediated up-regulation of FceRL Our preliminary data show that the human beta gene gives rise to two alternative transcripts that are co-expressed and encode two proteins with opposing functions: classical beta, and a newly described truncated protein, betaT. We will determine if betaT impacts IgE- mediated regulation. We will also assess if the alternative splicing to produce betaT is affected by the IgE-mediated regulation. Finally, we will ascertain whether known polymorphisms in the beta gene affect the alternative splicing of beta.
Specific Aim 4 : Dissect the minimal structure of FceRI required for IgE-mediated regulation. Having identified the molecular mechanism(s) that underlie IgE-mediated regulation of FcERI, we will determine the minimal structural basis for these mechanisms. We will identify the amino acid sequences in the alpha chain that are necessary to mediate up-regulation by using a number of mutated and chimeric receptors. In addition, we will determine if gamma impacts up-regulation utilizing a similar strategy. Finally, we will verify that the critical domains required for up-regulation affect the mechanism(s) of IgE-mediated FceRI up-regulation revealed in Aim 1. Taken together, these analyses will provide significant insights into the process and molecular parameters that control the IgE-mediated regulation of FceRI expression.
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