# BMAL1/ARNTL plays a critical, non-circadian role in secondary tissue damage after contusive SCI

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2020 · $513,423

## Abstract

Circadian rhythms regulate a wide spectrum of biological processes of critical importance for organismal
health. Perturbations of those rhythms underlie many pathologies including systemic inflammation, depression,
and neurodegeneration. Mechanistically, circadian rhythms are driven by intrinsic oscillatory changes in gene
expression that are orchestrated by several regulators of gene transcription and mRNA translation forming the
core oscillator circuitry. Those key regulators, most importantly the non-redundant transcription/translation
factor BMAL1/ARNTL, are active in most cells throughout the body and undergo circadian entrainment by
external time cues such as light or feeding. At the organismal level, the pro-rhythmic role of the oscillator is
widely recognized as a critical contributor to homeostasis. BMAL1 effects that are independent of the central
rhythm include anti-oxidant protection in the brain, life span regulation, contributions to atherosclerosis and
endoplasmic reticulum (ER) stress-sensitization of cancer cells. Those, or similar, tissue-specific functions of
BMAL1 may affect the outcome after SCI. However, clock function at the molecular level has never been
investigated in the context of SCI. Unexpectedly, we found that: (i) moderate contusive thoracic SCI
upregulates BMAL1 in penumbral oligodendrocytes (OLs), coinciding with induction of the ER stress response
(ERSR)-activated pro-apoptotic transcription factor CHOP and ER stress-mediated apoptosis of OLs, (ii) after
SCI, Bmal1-/- mice show improved locomotor recovery and white matter sparing (WMS), as well as selective
downregulation of Chop and its pro-apoptotic target gene death receptor 5 (Dr5) and reduced blood
extravasation and inflammation, with extensive changes in microglia/macrophage (MM) and endothelial (EC)-
specific gene expression. Also, pharmacological enhancement of the negative feedback inhibition of BMAL1
reduces ER stress toxicity in OPC cultures. These exciting findings suggest a novel role of BMAL1 in the
pathogenesis of SCI which may include OL-cell autonomous regulation of CHOP-mediated OL apoptosis
and/or EC/MM-cell autonomous modulation of post-SCI hemorrhage/vascular dysfunction/cytotoxic neuro-
inflammation. Therefore, we will test the hypothesis that BMAL1 regulates OL, EC, and/or MM gene expression
that contributes to SCI-associated white matter loss and impaired locomotor recovery. To test this hypothesis,
we will: (i) determine the cell autonomous roles of OL-, MM-, and EC-BMAL1 in SCI-associated white matter
damage and locomotor recovery, (ii) identify mechanism(s) that underlie BMAL1-mediated enhancement of
SCI-driven white matter loss, and (iii) evaluate mediators of the negative feedback inhibition of BMAL1 as
pharmacological targets for interventions to reduce SCI-associated white matter loss and locomotor
impairment. We will use a moderate T9 SCI contusion model in wild type or cell type-selective Bmal1-/- mice
and non-toxic, CNS-permeabl...

## Key facts

- **NIH application ID:** 10058531
- **Project number:** 1R01NS114404-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** MICHAL HETMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $513,423
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058531

## Citation

> US National Institutes of Health, RePORTER application 10058531, BMAL1/ARNTL plays a critical, non-circadian role in secondary tissue damage after contusive SCI (1R01NS114404-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10058531. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*