# NIH grant: Timing-dependent role of CRAC channels in Th17 metabolism and effector function (1R21AI201639-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21AI201639-01)

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NIH grant 1R21AI201639-01: Timing-dependent role of CRAC channels in Th17 metabolism and effector function
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Yousang  Gwack. Award: $196875.
Start: 2026-07-03T00:00:00.
PROJECT SUMMARY
Ca2+ influx through CRAC (Ca2+ release-activated Ca2+) channels is essential for T cell activation, differentiation,
and effector function. While prior studies have largely focused on their role in the initial activation of T cells, little
is known about the timing-dependent functions of CRAC channels during later phases of immune responses.
This represents a critical gap in knowledge with direct therapeutic implications, as interventions targeting CRAC
channels are being explored for autoimmune diseases. Our preliminary studies reveal that delayed inhibition of
CRAC channels, rather than early inhibition, profoundly impairs Th17 effector functions by reprogramming their
metabolism. In the experimental autoimmune encephalomyelitis (EAE) model, transient CRAC channel blockade
reduced disease severity without disrupting the core transcriptional program of Th17 differentiation.
Mechanistically, temporal inhibition induced the expression of the MYC antagonists MXD1 and MXD2, which
sequester MAX away from MYC, thereby suppressing IL-17 production. Importantly, we confirmed this effect in
human Th17 cells, highlighting the translational potential of this approach. The central hypothesis of this project
is that Ca2+ signaling during the delayed phase of T cell activation regulates the MYC-MXD axis to shape
metabolic programs critical for Th17 effector function. The proposed studies (1) will test the therapeutic potential
of temporal CRAC channel inhibition in autoimmunity using pharmacological and genetic approaches and (2)
will define the distinct contributions of MXD family members in modulating MYC activity, cellular metabolism, and
Th17 responses. This research is significant because it introduces timing as a key determinant in targeting Ca2+
signaling pathways for therapy and identifies MXD proteins as critical regulators of T cell metabolism and
function. It is innovative because it challenges the conventional view that CRAC channels act primarily during
the initial activation phase and instead establishes their essential role in the delayed phase of effector
programming. By uncovering how CRAC signaling and MXD regulation intersect to control Th17 responses, this
work will provide new insights into immune regulation and open avenues for precise and safer therapeutic
strategies for autoimmune diseases.
```



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