# Calcium release-activated calcium (CRAC) channels in experimental traumatic brain injury

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2024 · —

## Abstract

This project will explore calcium-release-activated calcium channels (CRAC) as a potential
therapeutic target in a laboratory model of traumatic brain injury (TBI). TBI is a common problem in
the Veteran and civilian populations but definitive treatments are few. Microglia are the brain’s
resident immune cell, and many studies have now shown that when activated, they contribute
negatively to neurological outcome. Thus, strategies to inhibit microglial functions could prove
therapeutic. Recent work has focused on the role of CRAC channels in inflammatory cells such as T
cells, mast cells and neutrophils, and other inflammatory conditions such as autoimmune disease and
acute pancreatitis; however, very little work has been published on CRAC channels as they pertain to
microglia or inflammation in the brain. Past work has focused on calcineurin inhibitors such as
cyclosporine A and FK 506 which act downstream of the CRAC channel, but have many off target
effects and clinical toxicities which limit their use. These CRAC channel inhibitors are already being
studied at the clinical level for other indications, and do not appear to have the same toxicities as the
CNIs. In fact, a similar inhibitor produced by the same company was recently shown to improve
outcome from severe COVID-19 pneumonia following infection with the SARS-CoV-2 virus, and was
well tolerated in this patient population. Prior work in our lab showed that these specific CRAC
channel inhibitors block microglial activation and that at least one of these inhibitors protects the brain
from experimental TBI. This project will study CRAC channel inhibitors in a model of TBI to further
define the conditions where neuroprotection may be observed. The first Aim will determine the more
protective of two such novel CRAC channel inhibitors, and determine the optimal dosing required for
maximum neurological benefit. This aim will also validate the specificity of the inhibitors and the
expected mechanism of action of downstream calcium and inflammatory signaling. The second aim
will then determine whether treatment can be delayed by hours and still show improvement in
neurological outcomes. The third aim will then use the optimal dose and dosing regimen determined
from the first two aims to see if any benefit is long lasting. In vivo experiments will include studies in
female animals as well as comparing these novel, specific inhibitors to currently available, but less
specific inhibitors.

## Key facts

- **NIH application ID:** 10695659
- **Project number:** 1I01BX004686-01A2
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Midori A Yenari
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695659

## Citation

> US National Institutes of Health, RePORTER application 10695659, Calcium release-activated calcium (CRAC) channels in experimental traumatic brain injury (1I01BX004686-01A2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10695659. Licensed CC0.

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