SBIR-STTR Award

Novel Approach for Developing Antibody Reagents to Probe Changes in the Synapse P
Award last edited on: 11/7/19

Sponsored Program
SBIR
Awarding Agency
NIH : NIDA
Total Award Amount
$1,786,954
Award Phase
2
Solicitation Topic Code
-----

Principal Investigator
Xiaomin Fan

Company Information

AvantGen Inc

10151 Pacific Mesa Boulevard Suite 103
San Diego, CA 92121
   (858) 768-8107
   xfan@avantgen.com
   www.avantgen.com
Location: Single
Congr. District: 52
County: San Diego

Phase I

Contract Number: 1R44DA035531-01
Start Date: 5/1/13    Completed: 4/30/14
Phase I year
2013
Phase I Amount
$224,957
The development of addiction involves the dopaminergic reward pathway and downstream negative changes that lead to craving and repeat self-administration. While it is clear this process involves changes in neuronal plasticity t the synapse junction, the exact changes at the protein level leading to the development of dependence and negative responses associated with withdrawal are poorly understood, in large part because of the highly complex cellular and tissue organization and neuronal circuitry within the brain. To better understand this process requires proteomic approaches, which in turn require better detection reagents for the synapse proteome which comprises over 2,000 different proteins. We propose to use our proprietary yeast display antibody library to develop well-characterized, high-affinity, specific antibodies against a panel of synapse proteins, many of which have been shown to be modulated in response to opiate administration. In this Phase I/II study, antibodies against a panel of about 150 synaptic proteins will be developed and used to probe the changes of these proteins upon drug administration in a mouse model. The long-term goal is to develop novel and high quality detection reagents for the entire synapse proteome with our yeast display/antibody library system to better map the critical changes underlying addiction.

Public Health Relevance Statement:


Public Health Relevance:
Drug addiction represents a major health issue, affecting 9% of the population over 12 years old in the US. While the initial sites that different drugs (includng alcohol) bind are known, much less is known about the way these drugs hijack the dopamine reward pathway within the brain and, through changes in signals sent within the brain's circuitry, induce ol ng-term changes that lock in dependence and the negative responses associated with craving and withdrawal symptoms. The complex and specialized nature of the brain requires that an extensive panel of detection agents against all the proteins found in nerve terminals (synapses) responsible for relaying the signals are developed before the critical molecular changes controlling these processes can be better understood and new therapies can be developed to counter addiction. The applicant organization has developed a system in yeast to support rapid identification of high quality antibodies, and will apply this technology to identify reagents for 150 of the ~2000 proteins found within synapses during this Phase I/II study. The collaborating laboratory will test these antibodies in murine models of opiate addiction to better map the critical changes at the protein level that control opiate addiction.

Project Terms:
12 year old; addiction; Affect; Affinity; Alcohols; Aliquot; Antibodies; Antibody Affinity; Antigens; base; Binding (Molecular Function); Biological Assay; Brain; Budgets; Cell Separation; Cells; Chimeric Proteins; Complex; craving; Custom; Dependence; Detection; Development; Dopamine; Drug Addiction; Drug or chemical Tissue Distribution; Enzyme-Linked Immunosorbent Assay; Epitopes; Escherichia coli; experience; expression vector; Fluorescence-Activated Cell Sorting; Generations; Genes; Goals; Harvest; Health; Human; Immunoglobulin Variable Region; Immunoprecipitation; improved; Individual; Kinetics; Label; Laboratories; Lead; Libraries; magnetic beads; Maps; Methods; Modeling; Molecular; Morphine; Morphine Dependence; mouse model; Mouse Protein; Mus; Nature; Nerve; neuronal circuitry; Neuronal Plasticity; novel; novel strategies; Opiate Addiction; Opiates; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; phase 1 study; phase 2 study; Population; Process; Production; Proteins; Proteome; Proteomics; Protocols documentation; public health relevance; Reagent; Research; response; Rewards; Sampling; Self Administration; Signal Transduction; Site; Sorting - Cell Movement; Specificity; Synapses; System; Technology; Testing; Time; Tissue Sample; Tissues; tool; Western Blotting; Withdrawal; Withdrawal Symptom; Yeasts

Phase II

Contract Number: 4R44DA035531-02
Start Date: 5/1/13    Completed: 2/28/17
Phase II year
2015
(last award dollars: 2016)
Phase II Amount
$1,561,997

The development of addiction involves the dopaminergic reward pathway and downstream negative changes that lead to craving and repeat self-administration. While it is clear this process involves changes in neuronal plasticity t the synapse junction, the exact changes at the protein level leading to the development of dependence and negative responses associated with withdrawal are poorly understood, in large part because of the highly complex cellular and tissue organization and neuronal circuitry within the brain. To better understand this process requires proteomic approaches, which in turn require better detection reagents for the synapse proteome which comprises over 2,000 different proteins. We propose to use our proprietary yeast display antibody library to develop well-characterized, high-affinity, specific antibodies against a panel of synapse proteins, many of which have been shown to be modulated in response to opiate administration. In this Phase I/II study, antibodies against a panel of about 150 synaptic proteins will be developed and used to probe the changes of these proteins upon drug administration in a mouse model. The long-term goal is to develop novel and high quality detection reagents for the entire synapse proteome with our yeast display/antibody library system to better map the critical changes underlying addiction.

Public Health Relevance Statement:


Public Health Relevance:
Drug addiction represents a major health issue, affecting 9% of the population over 12 years old in the US. While the initial sites that different drugs (includng alcohol) bind are known, much less is known about the way these drugs hijack the dopamine reward pathway within the brain and, through changes in signals sent within the brain's circuitry, induce ol ng-term changes that lock in dependence and the negative responses associated with craving and withdrawal symptoms. The complex and specialized nature of the brain requires that an extensive panel of detection agents against all the proteins found in nerve terminals (synapses) responsible for relaying the signals are developed before the critical molecular changes controlling these processes can be better understood and new therapies can be developed to counter addiction. The applicant organization has developed a system in yeast to support rapid identification of high quality antibodies, and will apply this technology to identify reagents for 150 of the ~2000 proteins found within synapses during this Phase I/II study. The collaborating laboratory will test these antibodies in murine models of opiate addiction to better map the critical changes at the protein level that control opiate addiction.

NIH Spending Category:
Biotechnology; Brain Disorders; Drug Abuse (NIDA only); Neurosciences; Substance Abuse

Project Terms:
12 year old; addiction; Affect; Affinity; Alcohols; Aliquot; Antibodies; Antibody Affinity; Antigens; base; Binding (Molecular Function); Biological Assay; Brain; brain circuitry; Budgets; Cell Separation; Cells; Chimeric Proteins; Complex; craving; Custom; Dependence; Detection; Development; Dopamine; Drug Addiction; Drug or chemical Tissue Distribution; Enzyme-Linked Immunosorbent Assay; Epitopes; Escherichia coli; experience; expression vector; Fluorescence-Activated Cell Sorting; Generations; Genes; Goals; Harvest; Health; Human; Immunoglobulin Variable Region; Immunoprecipitation; improved; Individual; Kinetics; Label; Laboratories; Lead; Libraries; magnetic beads; Maps; Methods; Modeling; Molecular; Morphine; Morphine Dependence; mouse model; Mouse Protein; Mus; Nature; Nerve; neuronal circuitry; Neuronal Plasticity; novel; novel strategies; Opiate Addiction; Opiates; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; phase 1 study; phase 2 study; Population; Process; Production; Proteins; Proteome; Proteomics; Protocols documentation; Reagent; Research; response; Rewards; Sampling; Self Administration; Signal Transduction; Site; Sorting - Cell Movement; Specificity; Synapses; System; Technology; Testing; Time; Tissue Sample; Tissues; tool; Western Blotting; Withdrawal; Withdrawal Symptom; Yeasts