Breaking a paradigm? Melanopsin, a canonical photo-pigment, acting as sensor to entrain the clock in light unexposed organs, and its putative interaction with TRP channels: a trans-disciplinary study involving physiological and pathological aspects

• Grant number: 17/24615-5
• Support Opportunities: Research Projects - Thematic Grants
• Duration: October 01, 2019 - September 30, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Ana Maria de Lauro Castrucci
• Grantee: Ana Maria de Lauro Castrucci
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais:( Atuais ): Miriam Oliveira Ribeiro
• Pesquisadores principais:( Anteriores ): Miguel Luiz Batista Junior
• Associated researchers: Adilson Luiz Guilherme ; Antonio Carlos Bianco ; Carlos Frederico Martins Menck ; Ignacio Provencio ; José Cipolla Neto ; Leonardo Vinícius Monteiro de Assis ; Maria Fernanda Pereira de Araújo Demonte Forni ; Maria Nathália de Carvalho Magalhães Moraes Figueira Borges ; Mauro Cesar Isoldi ; Niels Olsen Saraiva Câmara
• Associated scholarship(s): 22/04584-6 - ROLE OF THE TRANSIENT RECEPTOR POTENTIAL CHANNEL TRPA1 IN OBESITY. A NEW THERAPEUTIC TARGET?, BP.DR; 22/06190-5 - Breaking a paradigm? Melanopsin, a canonical photo-pigment, acting as sensor to entrain the clock in light unexposed organs, and its putative interaction with TRP channels: a trans-disciplinary study involving physiological and pathological aspects, BP.TT; 21/01659-2 - Participation of melanopsin in the thermoregulation of mammals, BP.MS; 20/04524-8 - Integrating proteogenomics approach and system biology to investigate the role of melanopsin and TRP channels in the circadian rhythmicity, BP.PD; 20/04576-8 - Breaking a paradigm? Melanopsin, a canonical photo-pigment, acting as sensor to entrain the clock in light unexposed organs, and its putative interaction with TRP channels: a trans-disciplinary study involving physiological and pathological aspects, BP.TT

Abstract

Based on preliminary data and on the amount of evidence produced by our group, this research project will investigate the following hypothesis: melanopsin (OPN4) and/or Transient Receptor Potencial channels (TRPs), expressed by cardiomyocytes, monitor among other putative signals, the variation of the core temperature and/or the local metabolic variation. We suggest that temperature variation would be brought about by the oxygenated blood entering the heart from the respiratory system, and the blood coming from the periphery, with lower pressure and poor in oxygen, in addition to the circadian variation of internal temperature. The temperature variation, or the metabolic alteration induced by the temperature change, would be translated by the heart, for instance, in the expression of its major hormones, Natriuretic Peptides (NPs) among others, to regulate local clocks and the metabolism of target organs such as White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT), and of the heart itself. Once we assumed a link (through NPs) between cardiac function and metabolism, and between metabolic disfunction and clock disruption (Tables 1, 2 and 3), we may speculate that the unbalance of this machinery would be responsible for pathologies not only in the heart itself, but in the whole organism. To understand how this circuitry is affected in metabolic extremes such as Obesity and Cachexia will open the possibility of intervention in the pathological syndromes, or in the prevention or mitigation of those alterations. We will evaluate how temperature, or metabolic alteration, is sensed, the local clocks and the canonical tissue-specific processes in vivo, and in tissue explants or cell culture of the suprachiasmatic nucleus (SCN), médio-basal nucleus, heart, WAT and BAT of WT and ²1 adrenoceptor, Opn4, TrpV1, TrpM8 and TrpA1 KO mice, in physiological conditions and in the metabolic extremes of obesity and cachexia, associated with assays of temperature variation. Initially, we will obtain the transcriptome of the mentioned organs from WT mice subject to 22°C (cold challenge) and to 30°C (thermo-neutrality), what will allow us to focus the investigation in the pathways and signaling of sensation altered by the temperature challenge. The in vivo assays will be performed at 22°C (or 8°C below the thermoneutral temperature determined in the other genotypes by indirect calorimetry) and 30°C (or other temperature for thermo-neutrality found for the other genotypes) and the in vitro assays at 34 and 37°C for WT mice (or other range of maximal circadian temperature, and 3 degrees below, to be determined for the altered genotypes); some assays will be conducted in the presence of agonists and antagonists of OPN4 and TRP channels, or in CRISPER KO cells. In the in vivo experiments, we will perform telemetry of locomotor activity and core temperature, and calorimetry. We will analyze clock genes and the tissue-specific genes identified by the comparative transcriptoma, using among others the following techniques: immunocytochemistry, quantitative PCR, Western blot, flow cytometry with image, CRISPER. Along the duration of the project, we intend to establish the strain of organ-specific Opn4 KO with Cre-lox system. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MARCONDES, A. A. E.; GOMEZ, T. G. B.; RAVACHE, T. T.; BATISTUZZO, A.; LORENA, F. B.; DE PAULA, C. S.; LOWENTHAL, R.; BIANCO, A. C.; RIBEIRO, M. O.. Assessment of children in the autistic spectrum disorder that carry the Thr92Ala-DIO2 polymorphism. Journal of Endocrinological Investigation, v. 44, n. 8, p. 1775-1782, AUG 2021. (17/24615-5)

SUA-CESPEDES, CRISTHIAN D.; DAVID, DANIELA DANTAS; SOUTO-NETO, JOSE A.; LIMA, OTONIEL GONCALVES; MORAES, MARIA NATHALIA; DE ASSIS, LEONARDO V. MONTEIRO; CASTRUCCI, ANA MARIA DE LAURO. Low Temperature Effect on the Endocrine and Circadian Systems of Adult Danio rerio. FRONTIERS IN PHYSIOLOGY, v. 12, NOV 24 2021. (18/23043-0, 18/16511-8, 17/26651-9, 18/14728-0, 17/24615-5, 18/23915-8)

DE ASSIS, LEONARDO VINICIUS MONTEIRO; TONOLLI, PAULO NEWTON; MORAES, MARIA NATHALIA; BAPTISTA, MAURICIO S.; CASTRUCCI, ANA MARIA DE LAURO. ow does the skin sense sun light? An integrative view of light sensing molecule. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY C-PHOTOCHEMISTRY REVIEWS, v. 47, JUN 2021. (17/24615-5, 18/14728-0, 13/07937-8)

MORAES, MARIA NATHALIA; DE ASSIS, LEONARDO VINICIUS MONTEIRO; PROVENCIO, IGNACIO; CASTRUCCI, ANA MARIA DE LAURO. Opsins outside the eye and the skin: a more complex scenario than originally thought for a classical light sensor. Cell and Tissue Research, v. 385, n. 3, JUL 2021. (17/26651-9, 17/24615-5, 18/14728-0)

FORNI, MARIA FERNANDA; ALBERTO DOMINGUEZ-AMOROCH, OMAR; MONTEIRO DE ASSIS, LEONARDO VINICIUS; KINKER, GABRIELA SARTI; MORAES, MARIA NATHALIA; DE LAURO CASTRUCCI, ANA MARIA; SARAIVA CAMARA, NIELS OLSEN. An Immunometabolic Shift Modulates Cytotoxic Lymphocyte Activation During Melanoma Progression in TRPA1 Channel Null Mice. FRONTIERS IN ONCOLOGY, v. 11, MAY 10 2021. (18/16511-8, 18/14728-0, 17/16711-4, 17/26651-9, 17/24615-5)

MONTEIRO DE ASSIS, LEONARDO VINICIUS; MENDES, DAVI; SILVA, MATHEUS MOLINA; KINKER, GABRIELA SARTI; PEREIRA-LIMA, ISABELLA; MORAES, MARIA NATHALIA; MARTINS MENCK, CARLOS FREDERICO; DE LAURO CASTRUCCI, ANA MARIA. Melanopsin mediates UVA-dependent modulation of proliferation, pigmentation, apoptosis, and molecular clock in normal and malignant melanocytes. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1867, n. 10, OCT 2020. (14/27287-0, 19/19435-3, 13/24337-4, 17/24615-5, 12/50214-4, 18/16511-8, 17/26651-9, 17/18781-0, 18/14728-0, 17/24217-0)

DE ASSIS, LEONARDO VINICIUS MONTEIRO; MORAES, MARIA NATHALIA; MENDES, DAVI; SILVA, MATHEUS MOLINA; MENCK, CARLOS FREDERICO MARTINS; CASTRUCCI, ANA MARIA DE LAURO. Loss of Melanopsin (OPN4) Leads to a Faster Cell Cycle Progression and Growth in Murine Melanocytes. CURRENT ISSUES IN MOLECULAR BIOLOGY, v. 43, n. 3, p. 1436-1450, DEC 2021. (18/16511-8, 17/24615-5, 17/26651-9, 17/18781-0, 19/19435-3, 18/14728-0, 17/24217-0)