| Title: |
Defining Pharmacodynamic Gene Markers and the Biological Processes of INPP5D Modulation Across Experimental Models |
| Authors: |
Matharu, Roma; Soni, Disha; Lin, Peter; Caballero-Floran, Isaac; Lamb, Bruce; Rangel-Barajes, Claudia; Oblak, Adrian |
| Source: |
Proceedings of IMPRS; Vol. 8 No. 1 (2025) ; 2641-2470 |
| Publisher Information: |
Indiana Medical Student Program for Research and Scholarship |
| Publication Year: |
2026 |
| Collection: |
Indiana University - Purdue University Indianapolis (IUPUI): E-Journals |
| Description: |
Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tau tangles. Microgliarespondto these pathological features but often become functionally impaired as the disease advances. INPP5D (also known as SHIP1),a phosphatase broadly expressed in hematopoietic cells and restricted to microglia within the brain, plays a key inhibitory role in regulating microglial activity. It acts through receptors such as TREM2, Dectin-1, andFcγRvia the PI3K/AKT signaling axis. Preclinical studies suggest that inhibiting INPP5D enhances microglial function and reduces AD-related pathology. To advance INPP5D-targeted therapies, it is essential to characterize the downstream transcriptional effects of inhibition.Identifyingconsistent gene expression changes across experimental models can help establish pharmacodynamic markers and clarify biological pathways to guide therapeutic development. Methods We investigated transcriptomic alterations associated with INPP5D inhibition using four models: (1) primary mouse microglia from Inpp5d haplodeficient versus wild-type mice (in vitro), (2) TAD32-treated versus vehicle-treated primary microglia (in vitro), (3) TAD32-treated versus vehicle-treated C57BL/6J mice (in vivo), and (4) INPP5D-targeting siRNA versus scrambled RNA-treated C57BL/6J mice (in vivo). Gene expression was profiled usingNanostring’sneuroinflammation and glial panels. Differentially expressed genes (DEGs) were compared across models toidentifyshared molecular signatures, and enrichment analysis was performed. Results Despite a limited overlap of individual DEGs, weobservedconsistent enrichment of key biological pathwaysrelated to phagocytosis (includingFcγRsignaling, lysosomal function, and complement activation), inflammatory regulation (TLR, IL-17, and TNF signaling), and PI3K/AKT signaling.These findings suggest that INPP5D inhibition elicits conserved functional effects across diverse experimental ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://journals.indianapolis.iu.edu/index.php/IMPRS/article/view/29727/26398; https://journals.indianapolis.iu.edu/index.php/IMPRS/article/view/29727 |
| Availability: |
https://journals.indianapolis.iu.edu/index.php/IMPRS/article/view/29727 |
| Rights: |
Copyright (c) 2026 Roma Matharu, Disha Soni, Peter Lin, Isaac Caballero-Floran, Bruce Lamb, Claudia Rangel-Barajes, Adrian Oblak ; http://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.50620BF0 |
| Database: |
BASE |