2004 — 2008 |
Weeber, Edwin John |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Reelin Signaling in the Adult Hippocampus
[unreadable] DESCRIPTION (provided by applicant): There is a functional connection between Apolipoprotein E (ApoE) and Alzheimer's disease. The underlying biochemical mechanism by which ApoE predisposes its carriers to this disease is not known and is under debate. One model suggests that members of a family of ApoE receptors that are abundantly expressed on the surface of neurons, specifically the ApoE2 and VLDL receptors, may be involved in this pathological process. Two of these ApoE receptors, the VLDL receptor and the ApoER2, are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. Adult expression of Reelin by GABA-ergic interneurons coupled to a high expression of ApoE2 and VLDL receptors in the hippocampus strongly suggests a role for these systems in adult CNS. The basis for this proposal is the hypothesis that there is a function of the Reelin/ApoE2/VLDL receptor system as a modulator of neurotransmission in the adult CNS. To better understand the role of this receptor system in mammalian hippocampal function, we will undertake four specific aims: [unreadable] Aim 1: Determine if mice deficient for ApoE2 and VLDL receptors exhibit deficits in learning and memory and hippocampal synoptic function. [unreadable] Aim 2: Determine the effect of Reelin application and Reelin signaling disruption on adult hippocampal synaptic transmission and plasticity. [unreadable] Aim 3: Test the hypothesis that Reelin acts through Src tyrosine kinase to phosphorylate NMDA receptors in an ApoER2/VLDL receptor-dependent manner. [unreadable] Aim 4: Determine the structure/function relationship for ApoER2 cytoplasmic domains. [unreadable] These studies will provide a basic understanding of the role for the lipoprotein receptors ApoE2 and VLDL in mammalian learning and memory mechanisms and hippocampal synaptic transmission and plasticity. Moreover, these studies will provide the first insight into the mechanisms of Reelin signaling through these receptors to modulate hippocampal function. Overall, this work will help shed light on the potential role of these ApoE receptors in neurodegenerative disorders, such as Alzheimer's disease. [unreadable] [unreadable]
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1 |
2009 — 2013 |
Weeber, Edwin John |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Apoe Signaling, Neurobehavior,and Neuroplasticity @ University of Illinois At Chicago
In the past decade, apoE has emerged as one of the best validated risk factors for late-onset, sporadic Alzheimer's disease (AD). Despite a great deal of research that has significantly improved understanding of apoE and its receptors, the mechanism by which apoE genotype influences an individual's predisposition to AD remains unknown. We know that specific lipoprotein receptors are essential in maintaining normal synaptic plasticity and learning and memory processes in the adult mouse hippocampus. The ligand- receptor interaction between apoE and its receptors is well poised in the molecular framework of the synapse to have broad implications for both normal cognitive processes and the perturbations observed in early AD. The overall hypothesis of this proposal states that that apoE acts as an isoform-specific signaling ligand to modulate neuronal synaptic plasticity and hippocampal-dependent memory formation, and is susceptible to changes in fi amyloid accumulation. The different apoE isoforms, the ligand reelin and the four prominent apoE receptors that bind these ligands adds an exceedingly complicated level of complexity to this system. This proposal is designed to better understand four important aspects of apoE signaling and apoE receptor function: 1) The circumstances that influence apoE receptor processing. 2) The mechanisms that underlie apoE-dependent changes in synaptic function and memory formation. 3) The interactions between specific apoE receptors and apoE isoforms in receptor signaling and processing. 4) The role of apoE isoform signaling and apoE receptor processing in the pathological processes associated with Alzheimer's disease. These studies will be the first to identify interactions of apoE isoforms to specific receptors and how those interactions can affect CNS function. These insights will be valuable in assessing AD risk, formulating new treatment strategies for AD, identifying potential therapeutic drug targets for the management of AD and provide insight into other age-related disorders involving the lipoprotein receptor system.
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0.948 |
2010 — 2011 |
Weeber, Edwin John |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Manipulating Temporal and Spacial Camkii Activity in Angelman Syndrome @ University of South Florida
DESCRIPTION (provided by applicant): Angelman Syndrome (AS) is a genetic neurological disorder that presents with seizure, ataxia, severe mental retardation, virtual absence of speech, and is genetically and biochemically associated with other cognitive disorders, such as autism and Rett syndrome. AS is caused by inactivation of the UBE3A gene in the brain due to various abnormalities of the 15q11-q13 chromosome inherited from the mother, including: a deletion of the region q11.2-q13 on the maternally inherited chromosome 15;a mutation in the UBE3A gene;paternal uniparental disomy in which the father contributes both copies of chromosome 15;an imprinting defect;or through an as yet unidentified mechanism. Work in our laboratory has centered upon identifying a molecular basis for the disease that lies downstream of UBE3A maternal deficiency. We recently demonstrated that genetic ablation of the auto-inhibitory site of 1CaMKII can rescue the major phenotypes of the Ube3a m-/p+ mouse. These results suggest that the major site of biochemical dysfunction in the AS mouse model is down- stream of CaMKII. This project is designed with the ultimate goal of establishing the basis for future rational development of human AS interventions. We present evidence which indicates that AS is potentially a treatable disorder. This exciting possibility is experimentally testable due in large part to the extraordinary utility of the Ube3a m-/p+ mouse model. We have developed three distinct therapeutic interventions to determine if the Ube3a m-/p+ mouse model phenotype can be rescued in a postnatal fashion through intervention (1) at the site of genetic abnormality, (2) at the downstream biochemical site of dysfunction, or (3) by directly modifying synaptic function. Our goal is to establish the preclinical viability of these therapeutic strategies, determine the temporal constraints for treatment and identify the optimal molecular targets for future human therapeutic research. PUBLIC HEALTH RELEVANCE: Angelman Syndrome (AS) is a genetic neurological disorder occurring in one in 12,000 populations. Independent living is not possible for adults with AS. The goals of this project are to establish the viability of three distinct therapeutic strategies to ameliorate the severe cognitive impairments exhibited by AS individuals.
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1 |
2010 |
Weeber, Edwin John |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Novel Therapeutic Strategies For Treatment of Angelman Syndrome @ University of South Florida
DESCRIPTION (Provided by Applicant): Angelman syndrome (AS) is a genetic neurological disorder that presents with seizure, ataxia, severe mental retardation, virtual absence of speech, and is genetically and biochemically associated with other cognitive disorders, such as autism and Rett syndrome. This project is designed with the ultimate goal of establishing the basis for future rational development of human AS interventions. The investigators present evidence which indicates that AS is potentially a treatable disorder. This exciting possibility is experimentally testable due in large part to the extraordinary utility of the Ube3am-/p+ mouse model. They have developed three distinct therapeutic interventions to determine if the Ube3am-/p+ mouse model phenotype can be rescued in a postnatal fashion through intervention (1) at the site of genetic abnormality, (2) at the downstream biochemical site of dysfunction, or (3) by directly modifying synaptic function. Because the availability of an effective treatment is often a criterion for inclusion of a condition on a newborn screening panel, their goal is to establish the preclinical viability of these therapeutic strategies, determine the temporal constraints for treatment, and identify the optimal molecular targets for future human therapeutic research. PROJECT NARRATIVE: Angelman syndrome (AS) is a genetic neurological disorder occurring in one in 12,000 population. Independent living is not possible for adults with AS. The goals of this project are to establish the viability of three distinct therapeutic strategies to ameliorate the severe cognitive impairments exhibited by AS individuals.
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1 |