# Project 3

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2024 · $980,914

## Abstract

Project 3: ABSTRACT
Smell deficits detected by established psychophysical measures are reproducibly reported in patients with
schizophrenia (SZ). Importantly, smell deficits are correlated with specific clinical features, such as negative
symptoms (e.g., avolition, anhedonia) and some cognitive deficits (e.g., social cognitive deficits), but not with
positive symptoms (e.g., hallucination, delusion). Smell deficits are found in SZ from the early stages of the
disease, and to a milder extent, in the first-degree relatives, indicating that smell deficits are a reflection of
fundamental disease pathophysiology rather than mere secondary outcomes of confounding factors (e.g.,
medications) in SZ. The olfactory epithelium (OE) is the most peripheral component of the olfactory system,
located outside the cranium. Thus, OE is highly influenced by environmental stressors, such as viral infection
and air pollution. Molecular changes in the OE in SZ have been reported from many groups. Nevertheless,
whether and how pathological changes in OE contributes to clinical manifestation in SZ still remains to be
elucidated. We have recently obtained evidence that immune/inflammatory changes associated with redox
imbalance may be one of the most prominent alterations in the OE pathology in SZ. Furthermore, we have
observed that the OE molecular changes (inflammation, redox) are significantly correlated with OB volume
changes and negative symptoms in SZ. In parallel, we observed that a mouse model of local chronic OE
inflammation affects the pyramidal neurons in the prefrontal cortex (PFC) and resultant behavioral changes
(including those in positive valence systems), which may be mediated by the olfactory-prefrontal circuits.
Based on these compelling evidence, we hypothesize that molecular and cellular changes in the OE
significantly contribute to specific clinical manifestations that correlate with smell deficits in SZ patients, which
is mediated by the olfactory-prefrontal circuits. We expect that OE pathology in SZ is a major contributory
mechanism for negative symptoms and social cognitive deficits. In this Project, we will define OE pathology in
SZ patients at the tissue level via immunohistochemistry and single-cell RNA sequencing (Aim 1). By
leveraging the homogeneity of olfactory neuronal cells (ONCs), we will further define OE pathology in SZ in
greater detail using bulk RNA sequencing and aim to identify key molecules for OE pathology in SZ (Aim 2).
By using the key molecules, we will aim to stratify SZ patients. Lastly, we will study the relationship between
OE pathology and anatomical/clinical characteristics in SZ (Aim 3). We will conduct correlation analysis and
mediation analysis by utilizing the multimodal data (OE, OB, PFC, and clinical data) from the same subjects.
We will also perform a longitudinal cohort maintenance. Through this study, we plan to establish the OE
pathology and its contributory role to negative symptoms and social cognitive def...

## Key facts

- **NIH application ID:** 10862178
- **Project number:** 1P50MH136297-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Akira Sawa
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $980,914
- **Award type:** 1
- **Project period:** 2024-04-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862178

## Citation

> US National Institutes of Health, RePORTER application 10862178, Project 3 (1P50MH136297-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862178. Licensed CC0.

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