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Description
The primary goal of our funded RF1 is to elucidate SHIP1 actions in Alzheimers disease (AD). Our global hypothesis is that a SHIP1 polymorphism increases SHIP1 expression, resulting in greater TREM2 inhibition and, thereby, increased AD risk. TREM2 signaling is mediated by an immunotyrosine activating motif (ITAM). Quite recently, we recognized a second ITAM pathway potentially modulating AD risk, and propose that SHIP1 acts by inhibiting this pathway as well. This novel pathway focuses on signaling from CD33, a sialic acid-binding receptor implicated in AD risk by genetics. We and others previously found that AD risk was reduced by a CD33 polymorphism that decreases CD33 exon 2 inclusion. Since exon 2 encodes the sialic acid binding domain, the CD33 isoform lacking exon 2 (D2-CD33) was considered a loss of CD33 function. However, we recently found a rare, 4 bp INDEL in CD33 exon 3, which precludes functional CD33 protein, and this loss of function INDEL is not associated with AD risk. Therefore, we currently hypothesize that D2-CD33 acts via a gain of function to protect from AD. In particular, careful comparison of the D2-CD33 cytosolic domain finds a near-consensus ITAM sequence. Hence, we propose that D2-CD33 acts as an ITAM and is inhibited by SHIP1. To evaluate this hypothesis, we will undertake the following Specific Aims (1) D2-CD33 acts as an ITAM, (2) SHIP1 binds phospho-D2-CD33 but not D2-CD33 and (3) SHIP1 inhibits D2-CD33 ITAM signaling to reduce microglial activation. Overall, this supplement to our primary RF1 project will test a novel mechanism for SHIP1 actions and represents a potential breakthrough in understanding AD genetic mechanisms.
Status | Finished |
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Effective start/end date | 9/15/18 → 8/31/23 |
Funding
- National Institute on Aging
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Projects
- 1 Finished
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Translating SHIP1 Genetics to Generate a Novel Alzheimers Pharmacologic Agent
Estus, G. (PI), Fardo, D. (CoI), Morganti, J. (CoI), Murphy, M. (CoI), Nelson, P. (CoI) & Van Eldik, L. (CoI)
9/15/18 → 8/31/23
Project: Research project