Genomic Editing to Elucidate CD33 Function

Grants and Contracts Details


The overarching theme of this proposal is that elucidating the mechanisms underlying single nucleotide polymorphisms (SNP)s robustly associated with Alzheimer disease (AD) risk will reveal pharmacologic targets. We recently reported that the AD-protective rs3865444A allele is associated with a significant ~10% per allele increase in the expression of CD33 lacking exon 2 (D2-CD33). Since D2-CD33 lacks the predicted sialic acid binding domain, we hypothesize that D2-CD33 encodes non-functional CD33 [1]. To evaluate this hypothesis, we propose the following Specific Aim: Generate microglial cells expressing only CD33 or D2-CD33 and compare for their ability to phagocytize Aß and for their cytokine production under baseline and inflammatory (LPS-stimulated) environments. For this effort, we will use CRISPR to alter CD33 exon 2 boundaries to make exon 2 splicing highly efficient or highly inefficient. Hence, this approach will allow a comparison of CD33 and D2-CD33 under conditions of endogenous protein expression. Overall, this proposal will develop our compelling mechanistic genetic results to provide insight into CD33 isoform function and serve as a prototype for evaluating functional polymorphisms derived from AD genome wide association studies.
Effective start/end date7/1/146/30/16


  • BrightFocus Foundation: $105,000.00


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