# Nicotinic receptor selective cell penetrating peptide for brain cargo delivery

> **NIH NIH R03** · UNIVERSITY OF ALASKA FAIRBANKS · 2024 · $77,500

## Abstract

ABSTRACT. In the U.S., major depressive disorder (MDD) is the most common mental disorder,
with depression prevalence approaching 20% among adolescents and young adults. Current
pharmacological treatments are unsatisfactory in that 33-55% of people suffering from MDD are
non-responsive. MDD is associated with alterations in neurotransmitter systems including
hypercholinergic tone modulated by nicotinic acetylcholine receptors (nAChRs) and decreased
brain-derived neurotrophic factor (BDNF) expression. nAChRs are abundant in the central
nervous system, and hypercholinergic tone, in part caused by α7-nAChR activation, is associated
with depression. Pharmacologically desensitizing α7-nAChRs improves depressive symptoms in
mice. Common serotonin and norepinephrine reuptake inhibitor therapies antagonize nAChRs
non-selectivity (off target effect) and enhance BDNF levels at clinically effective doses. Excitingly,
reducing expression of programmed cell death 4 (Pdcd4) protein, a translation inhibitor, by small
interfering RNA (siRNA) delivered by a cell penetrating peptide (CPP), enhances BDNF
expression to reverse depressive-like behaviors in mice. However, caution must be taken as
CPPs interact broadly with cellular macromolecules and lipid bilayers resulting in uncontrolled
cargo delivery. To begin to combat this issue, we developed an α7-nAChR selective CPP. Our
preliminary data show that the lead CPP is not cytotoxic and can transport a fluorophore into
neuronal-like cells by an α7-nAChR dependent mechanism. These underlying findings led us to
our hypothesis that the novel lead CPP, a selective α7-nAChR antagonist, coupled with Pdcd4
siRNA may be able to achieve our important goal to help those suffering from MDD. Defining if
the lead CPP can move siRNA cargo into cells and mammalian brain will remove critical barriers
that stymie scientific and clinical MDD work, in addition to other conditions affected by α7-nAChR
dysregulation. We will pursue the aims of this proposal by comparing cell culture and in vivo
application of the lead CPP complexed with fluorophore-tagged siRNA to determine if the siRNA
can be delivered to cause a cellular effect. We will combine live-cell confocal microscopy, brain
imaging, western blot, and ELISA assays. Anticipated outcomes may also reveal potential utility
of the lead CPP as a research tool. Application funding will provide foundational support for PI
Weltzin’s progress towards becoming an independent researcher by demonstrating project
feasibility, assay advancement, preliminary data generation, and a senior-author publication.

## Key facts

- **NIH application ID:** 10791300
- **Project number:** 1R03MH135358-01
- **Recipient organization:** UNIVERSITY OF ALASKA FAIRBANKS
- **Principal Investigator:** Maegan M Weltzin
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,500
- **Award type:** 1
- **Project period:** 2023-11-10 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791300

## Citation

> US National Institutes of Health, RePORTER application 10791300, Nicotinic receptor selective cell penetrating peptide for brain cargo delivery (1R03MH135358-01). Retrieved via AI Analytics 2026-07-01 from https://api.ai-analytics.org/grant/nih/10791300. Licensed CC0.

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