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Abstract
Grant Number: 1R03MH082367-01 Project Title: An HTS Assay Based on Neuronal Human Cells to Identify Small Molecule Activators
PI Information: Name Title GRIMALDI, MAURIZIO grimaldi@sri.org ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): Effective treatment for neurodegenerative diseases, such as Alzheimer's, is still lacking. Only, marginal symptomatologic treatment is available to data. Alzheimer's association and other Health agencies, including NIH, have estimated that the economic cost of Alzheimer's disease patients management in the sole USA amounts to billions. Also the psychological and material burden on the patients' families accounts for additional and consistent damage done by this devastating disease. Recent statistics have calculated that just slowing down the disease by a few years will have an enormous impact on the economics and social consequences of this tremendous disease. Although, considerable efforts and resources have been deployed in the research for the causes and for an effective treatment, a cure for this disease is far from being discovered. New ideas and approaches are needed, indeed. In this context our proposal is completely novel and can open a new field to advance both knowledge and possibilities to approach these conditions. There are several indications that NF-kB system plays a role in neuronal resilience and in the changes induced by cellular learning such as long term potentiation and depression. Several reports have shown that knocking out NF-kB activity in the brain causes sensitization to toxic stimuli, such as a-amyloid, and excitatory aminoacids and to trauma. In addition, activation of NF-kB is a known anti-apoptosis mechanism. Based on these premises, we believe there is room to investigate the possibility that NF-kB up regulation could be of value in mitigating both neurodegenerative phenomenon and learning and memory failure, a unique possibility. We have developed an original neuronal cell-based assay that will assess NF-kB up-regulation using a luciferase reporter. We propose to use this assay to perform a high throughput screen of small molecules libraries available to us. We will screen these library to identify small molecules able to increase NF-kB expression (usually 2-5% of the total compounds, will turn out as hits). We plan to follow up the screening with in vitro validation of the selected compounds on a number of parameters which will include NF-kB expression, function, in vitro neurotoxicity paradigms to verify that the identified compounds have, in fact, a neuroprotective and/or a neurotrophic effect. We believe that as a result of the proposed studies we will have identified 1) novel small molecules that can be used as research tools to study the effects of NF-kB on signaling pathways; 2) possible drug leads that can serve as a launch pad for a larger effort aiming to develop and test active and safe compounds to help in the battle against neurodegenerative disorders. Treatment options for Alzheimer's and other neurodegenerative disorders are fairly limited. They are usually symptomatic rather than curative, and in general their effectiveness is poor. Statistics from the Alzheimer's association and from the NIH have assessed that the cost for the management of this patients rises to billions. An important part of the socially debilitating effect of these disorders is the consequences, both economic and psychological, on the families. This is due to both the expensive long term care and to the witnessing of the effect that these devastating disorders have on their loved one. It has been calculated that if the progression of Alzheimer disease could be delayed even by a few years the repercussions both at economic and psychological level will be enormous. Recent evidence have pointed out that NF-kB signaling system is involved in the resilience of neurons and in their ability to survive disparate insults and in neuronal molecular correlates of learning and memory. NF-kB molecular ablation has shown that neurons from these animals are more sensitive to insults including trauma, a-amyloid toxicity and excitotoxicity. Also a direct neuroprotective effect from both non apoptotic and apoptotic models of neurodegeneration has been attributed to direct or indirect activation of NF-kB signaling. In addition, NF-kB signaling has been involved in the establishment of long term potentiation and long term depression, two models of learning and memory that take place at cellular level. Therefore, NF-kB up regulation in neurons could be useful in attacking at the same time neuronal degeneration and deterioration of neuronal functions associated with loss of learning and memory as seen in Alzheimer's disease. To pursue this grand scope, we have developed an original neuronal cell-based assay that will assess NF-kB up-regulation using a lucipherase reporter. We propose to use this assay to perform a high throughput screen of small molecules libraries available to us. We will screen this library to identify small molecules able to increase NF-kB expression (usually 2-5% of the total compounds, will turn out as hits). We will follow up the screening with in vitro testing of the selected compounds on a number of parameters which will include NF-kB expression, function, in vitro neurotoxicity paradigms to verify that the identified compounds have, in fact, a neuroprotective and/or a neurotrophic effect. We believe that as a result of the proposed studies we will have identified 1) novel small molecules that can be used as research tools to study the effects of NF-kB on signaling pathways; 2) possible drug leads that can serve as a launch pad for a larger effort aiming to develop and test active and safe compounds to help in the battle against neurodegenerative disorders.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
drug discovery /isolation, high throughput technology, neural degeneration, neuropharmacology, neuroprotectant, nuclear factor kappa beta
brain disorder, learning, luciferin monooxygenase, memory, small molecule, technology /technique development
NIH Roadmap Initiative tag, bioassay, biotechnology, cell line, human tissue
Institution: SOUTHERN RESEARCH INSTITUTE 2000 NINTH AVENUE SOUTH BIRMINGHAM, AL 35205 Fiscal Year: 2007 Department: Project Start: 27-AUG-2007 Project End: 31-JUL-2009 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZMH1