# NIH grant: Development of a multi-modal mouse model of cluster headache (1R61NS144491-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R61NS144491-01A1)

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NIH grant 1R61NS144491-01A1: Development of a multi-modal mouse model of cluster headache
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Mark J Burish. Award: $399725.
Start: 2026-06-18T00:00:00.
PROJECT SUMMARY / ABSTRACT
Cluster headache (CH), which affects about 1 in 1,000 people, is a severe and debilitating primary headache
disorder characterized by repeated attacks occurring in clusters over weeks or months. CH has clearly defined
features: severe pain (worse than childbirth), facial autonomic changes (such as a watery eye), restlessness,
and a striking circadian pattern of attacks (at the same time each day like clockwork in approximately 70.5% of
patients). CH also has a well-defined pathophysiology of 3 systems: the trigeminovascular pain system, the
autonomic nervous system, and the hypothalamic system (in particular the posterior hypothalamus, the first brain
area activated during an attack). Despite the well-known features and systems involved in CH, no disease-
specific treatments are available: all CH treatments are repurposed medications from other diseases. This lack
of CH-specific treatments is due in large part to the lack of a viable animal model that faithfully recapitulates the
aforementioned CH features. To develop a specific animal model for CH, we previously studied a
trigeminovascular headache model (repeated nitroglycerin injections), and discovered a circadian pattern of pain
responses that reflects the clockwork-like pattern of attacks in CH patients. Furthermore, our analysis also
identified a recently discovered CH modifier gene Mertk (MER proto-oncogene, tyrosine receptor kinase) to be
highly rhythmically expressed in the trigeminal ganglion. Deletion of Mertk (Mertk-KO) altered the normal
circadian rhythm of pain sensitivity by increasing pain sensitivity over 24 hours. Finally, activation of the posterior
hypothalamus (via c-Fos staining) was observed after NTG administration in wild-type mice. Based on these
exciting preliminary findings, we hypothesize that a combination of trigeminovascular (nitroglycerin), genetic
(Mertk-KO), and hypothalamic (direct optogenetic activation of the posterior hypothalamus) manipulations will
generate the first multi-modal animal model of CH. In Aim 1 (the R61 phase), we will determine the contributions
of each aspect of our combined model, alone or in combination (a 4x2 grid of NTG or control, Mertk KO mouse
or wild-type control, and optogenetic injection or control). Our milestone for progression to the R33 phase will be
significant differences in at least two pain behaviors in our model compared to controls. In Aims 2 and 3 (the R33
phase), we will validate our model through face validity (lacrimation and restlessness), construct validity (CGRP,
PACAP, and VIP in the trigeminal ganglion and hypothalamus), and predictive validity (ability of first-line and
new treatments to ameliorate the pain behaviors of our model). This project is highly significant and innovative,
addressing a profound need for a specific and comprehensive animal model for this devastating yet understudied
disease. With the unique combination of complementary expertise in CH (laboratory and clinical), circadian
biology, pharmacology, optogenetics and pain, we are ideally suited to generate this combined CH model with
the goal of providing insights into CH pathophysiology and developing novel therapeutics.
```



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