One gene associated with ADHD is LPHN3. Interestingly, the latrophilin protein was discovered through a coimmunoprecipitation of the alpha latrotoxin in black widow spiders venom. This gene encodes three isoforms; LPHN1, LPHN2, and LPHN3. LPHN3, an adhesion G-protein coupled receptor (GPCR), is almost exclusively expressed in the brain. Null and mutant LPHN3 leads to a loss in brain volume (3). Common ADHD medications rescue behavioral phenotypes in zebrafish (4), however little is known about the molecular mechanisms LPHN3 regulates in brain development and behavior.
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Specific Aim 2
The goal in my aim 2 is to identify small molecules that assist in brain development and can recover behavioral defects in LPHN3 mutants. In this aim I will use a focused chemical genetic screen, that targets GPCRs in particular, in order to discover small molecules that rescue LPHN3 mutants which have decreased brain development and ADHD like behavior. I will measure brain volume with the in vivo MRI and hyperactive behavior as well at each lifecycle stage to see if and when brain development and behavior can be recovered. |
Specific Aim 3
My goal in aim 3 is to identify protein-protein interactions responsible for proper brain development and behavior in LPHN3 mutants. To start I will collect brain tissue samples from mutant, mutant plus drug, and wild type zebrafish. I will be doing a co-immunoprecipitation and mass spectrometry at each life cycle stage of mutant, mutant treated, and wild type zebrafish. I will identify crucial protein interactions that are necessary for proper brain development and behavior. I will also identify if any small molecules are able to recover crucial protein interactions in mutant zebrafish. |
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adhdlphn3_brennansean_4-6-17.pptx | |
File Size: | 1697 kb |
File Type: | pptx |
sean_final_564.pptx | |
File Size: | 4039 kb |
File Type: | pptx |