# Alternative mechanisms of signaling via trimeric G proteins

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $330,000

## Abstract

We are requesting this Administrative Supplement to allow our currently funded R01 project to expand into
Alzheimer’s disease (AD) research. The currently funded project was not focused on AD, but recent
discoveries in this field have revealed an opportunity that we are uniquely positioned to pursue by leveraging
resources generated through the parental project. In the parental R01, we set out to characterize a new
molecular mechanism that regulates signal transduction in the context of neurotransmission. More specifically,
a protein we classified as a “paradoxical G protein regulator” (PGR) fine-tunes the responses triggered by G
protein-coupled receptors (GPCRs), a large group of neurotransmitter receptors. A salient feature of GPCRs is
that they are highly “druggable”— e.g., about a third of clinically used drugs target them, including numerous
medications for neurological diseases. Recent evidence has now established a connection between this PGR
and the progression of Alzheimer’s disease. We posit that further characterization of this connection would
pave the way for new therapeutic avenues in AD by identifying new pharmacologically actionable pathways
(like those mediated by GPCRs) in the molecular basis of this dementia. This would address a critical unmet
medical need because therapeutic options in Alzheimer's disease are very limited.
 Incidentally, the same PGR we were investigating in our parental project was recently identified in large-
scale (n>400 patients) brain proteomic studies as a protein that is downregulated in Alzheimer’s disease,
starting from the asymptomatic phase of the disease. Moreover, loss of this PGR in patients was also found to
correlate with age-dependent cognitive decline independently of AD status. These observations are exciting
because dysregulated neurotransmission underlies cognitive decline in AD, but the specific alterations and
mechanisms involved are not well understood. Our goal is to interrogate a causal relationship between loss of
PGR and age-dependent cognitive decline, and to map the brain proteomic changes that underlie this
relationship. We have gathered preliminary data suggesting that PGR knock-out mice have learning and
memory defects when they are one year old (middle age), but not when they are young. Our data also suggest
that these defects might be more pronounced in females than in males, an interesting feature that correlates
with the higher prevalence of AD in women. Motivated by these compelling preliminary results, we now
propose to expand our mouse behavioral studies by evaluating young, middle, and old age mice (4, 12, or 18
months, respectively). The experimental design will be powered to identify differences not only by age but also
by sex. In parallel, we will use quantitative proteomics and bioinformatics to assess global proteomic changes
in different brain regions across the experimental groups. We anticipate that this project will establish a
previously unappreciated causa...

## Key facts

- **NIH application ID:** 10498991
- **Project number:** 3R01NS117101-08S1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Mikel Garcia-Marcos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $330,000
- **Award type:** 3
- **Project period:** 2014-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498991

## Citation

> US National Institutes of Health, RePORTER application 10498991, Alternative mechanisms of signaling via trimeric G proteins (3R01NS117101-08S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10498991. Licensed CC0.

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