[R01] Allostery of RAMP-CLR Signaling in Vascular Cells During Migraine
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-11-30
Importo max: 2.676.945 EUR
Paese: US
Descrizione
Project Summary Abstract
This proposal builds on our long-standing interest and expertise in the functions of the
multifunctional G protein-coupled receptor (GPCR), calcitonin receptor-like receptor
(CLR=protein; Calcrl=gene) and its allosteric modulators, receptor activity modifying proteins
(RAMPs) 1, 2 and 3. CLR-RAMP signaling activated by adrenomedullin peptide is required for
the development and normal function of lymphatic vessels in mice and humans, while
activation by calcitonin gene related peptide (CGRP) represents a breakthrough
pharmacological target for migraine treatment. However, the cellular and signaling effects of
CLR-RAMPs in different lymphatic vascular beds, and under the regulation of female sex
hormones, has yet to be elucidated. Our preliminary data converge these signaling paradigms
into a promising molecular hypothesis on how RAMPs can allosterically modify CLR receptor
signaling in vascular cells to trigger and sustain the female-predominance of chronic migraine.
We plan to use sophisticated genetic mouse models coupled to in vitro pharmacological and
cell biological assays to address the integrative roles of RAMPs in vascular cells during
migraine. We anticipate that our findings will provide novel insights into the cell-specific
and hormonally-responsive processes that govern vascular CGRP signaling during
migraine and shed new light onto the pharmacological targets and actions of anti-CGRP
therapies commonly prescribed to treat migraine.
Istituzione: UNIV OF NORTH CAROLINA CHAPEL HILL
PI: Kathleen M Caron
Progetto: 1R01HL176992-01A1
Settori: National Heart Lung and Blood Institute
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