Grants and Contracts Details


Abstract: Genome wide association studies have robustly identified single nucleotide polymorphisms (SNP)s associated with Alzheimer disease (AD) risk. Our overarching theme is that these SNPs define mechanisms that are rate-limiting in AD development and thus represent targets for AD drugs. More specifically, we propose that drugs that amplify the actions of the protective SNP allele represent “genetically validated” pharmacologic agents. In this proposal, we will focus on rs35349669 (rs669), a common SNP within INPP5D that was strongly AD associated. INPP5D encodes a lipid phosphatase, SHIP1, which converts phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to PtdIns(3,4)P2. In our compelling preliminary results, we show that (i) INPP5D is expressed in microglia, and (ii) INPP5D expression increases with AD, and (iii) increases with the allele of rs669 that promotes AD risk. Although SHIP1 actions in microglia have not been evaluated, we previously reported that SHIP1 directly inhibits TREM2-mediated signaling in osteoclasts, a macrophage-type cell critical to bone homeostasis. To discern the role of SHIP1 in AD, we have developed SHIP1 conditional-deficient mice as well as small molecule SHIP1 inhibitors. Overall, this study brings together an interdisciplinary team to critically test our global hypothesis: SHIP1 inhibition decreases AD risk, whether inhibition is due to genetics or pharmacologic agents. To test our hypothesis, we propose the following Specific Aims: (1). Elucidate the mechanism underlying rs669, (2) Elucidate SHIP1 molecular actions relative to AD pathogenic mechanisms, (3) Define the optimal SHIP inhibition strategy to impact microglial function in the CNS and (4) Translate INPP5D genetics into a novel therapeutic agent. Overall, this focused proposal will develop our compelling molecular genetic results, elucidate the actions of SHIP1 in an AD context, and translate these changes into a possible AD-preventive agent.
Effective start/end date9/15/188/31/23


  • National Institute on Aging: $3,909,100.00


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