The integrins are heterodimer trans-membrane cell adhesion receptors with extracellular domains that bind extracellular matrix and cell surface proteins and cytoplasmic domains that are linked to cytoskeletal elements and activate signal transduction pathways. Little is known about the distribution, regulation and function of integrin proteins in adult brain although recent findings implicate these receptors in synaptic plasticity. Preliminary studies by the applicant have demonstrated that integrin subunit expression is high in areas of synaptogenesis and is regulated by neuronal activity. Moreover, pilot studies indicate that manipulation of integrin signaling alters the expression of neurotrophin genes. Together with previous reports of integrin involvement in long term potentiation, these findings suggest that the integrins are active in the mature brain and are associated with activity-dependent gene regulation and neuronal plasticity. The goals of the proposed research are to test this hypothesis. There are five specific aims.
Specific Aim 1 will use in situ hybridization to map integrin subunit mRNA expression in brain and test the hypothesis that subunits are differentially distributed across forebrain systems.
aims 2 and 3 will determine if synaptic activity regulates integrin turnover in adult brain. Studies will determine if activity induces mRNA expression (Aim 2) and protease-dependent degradation (Aim 3) of hippocampal beta1 integrin.
Aim 4 will test the hypothesis that pools of latent integrins exist in brain and these are activated by stimuli associated with intense physiological activity. Antisera specific for the active conformation of beta 1 integrin will be used to test the effects of electrical stimulation and proposed signaling molecules active in association with intense synaptic activity. Activation of latent integrins is a route used by various biological signals to modify anatomy and genomic expression in target cells but there is no evidence relating to the possible use of this mechanism in brain. The fifth aim is to determine if integrin receptors mediate or modulate activity-dependent changes in neurotrophic factor expression. Together, these studies will provide the first analysis in brain of the distribution, responsivity and trophic functions of a class of receptors critical to signal transduction in the periphery and may provide evidence for a novel mechanism of neurotrophic factor gene regulation associated with maturational changes in brain neurotrophism.
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