Project 3. Cyclic nucleotides (cAMP and cGMP) are intracellular signaling molecules that are critical for the development and function ofthe brain. Deficits in cAMP/cGMP signaling have been repeatedly measured in patients with Alzheimer's disease and schizophrenia. Dysfunction ofthe hippocampus (HIPP) - a brain region that modulates affective, social, stress-related, and cognitive behaviors - has also been repeatedly implicated in these neuropsychiatric diseases. We believe that selectively restoring cyclic nucleotide signaling in the HIPP of patients, without affecting signaling in normal brain regions, would relieve neuropsychiatric disease-related symptoms without causing unwanted side effects. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down both cAMP and cGMP. We have recently discovered that PDE11A is almost exclusively localized to the HIPP. Thus, we hypothesize that cAMP/cGMP signaling in the HIPP can be selectively targeted by modulating PDE11A expression and/or function. Adult PDE11A knockout (KO) mice exhibit biochemical, anatomical, and behavioral deficits that are consistent with HIPP dysfunction and neuropsychiatric disease. This suggests that augmentation of PDE11A function may prove therapeutic. To increase function of a particular enzyme, we can increase either its availability (i.e., expression) or its catalytic activity. As such, we propose a series of aims designed to understand the molecular mechanisms controlling transcription and catalytic activity of PDE11 A.
In Specific Aim 1, we will determine if psychiatric disease is associated with changes in PDE11A transcription in brain and if cis-acting elements within the promoter of PDE11A are sufficient to restrict PDE11A mRNA expression to the HIPP in the healthy adult brain.
In Specific Aim 2, we will identify the signaling cascades and trans-acting proteins that control PDE11A promoter activity.
In Specific Aim 3, we will develop small molecule PDE11A activators and test them in PDE11A wild-type and KO mice (KOs = negative controls) using a neuropsychiatric battery that assesses efficacy and side effect liability. PDE11A may be capable of selectively restoring cAMP and cGMP signaling in a specific brain region impacted by disease, without affecting signaling elsewhere.
Deficits in cAMP and cGMP signaling have been repeatedly measured in patients with Alzheimer's disease and schizophrenia. This proposal seeks to better understand how we can control the transcription and catalytic activity of Phosphodiesterase 11 A, an enzyme that breaks down cAMP and cGMP. In so doing, we hope to identify a therapeutic path forward to rescue the cAMP and cGMP deficits associated with neuropsychiatric diseases
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