Comparative analysis of subcompartimentalization of hypoglossal nucleus motor neurons mice and humans

• Grant number: 18/08758-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2018
• End date: February 28, 2021
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Luiz Ubirajara Sennes
• Grantee: Carla Freire de Castro Lima
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Obstructive Sleep Apnea (OSA) is a prevalent condition leading to high morbidity and mortality in the western world. The loss of motor input during sleep leads to pharyngeal collapse and the tongue has been identified as a key component of OSA pathogenesis. Continuous Positive Airway Pressure (CPAP) is considered the gold standard treatment, but it has poor adherence. There is no effective pharmacotherapy, and the efforts to develop novel treatments have been hindered by a lack of fundamental insight in molecular function of the neurons responsible for pharyngeal patency. Objectives: Our objectives are to identify specific subpopulations of tongue motoneurons in mice, morphometric characterization of the hypoglossal nerve nucleus of mice and of humans and comparison between findings in mice and humans. Identification of leptin signaling pathways in brainstem in humans.Materials and methods: Injection of B subunit of fluorescein-conjugated cholera toxin (CTB-AF) morphological analysis of motoneurons in the hypoglossal nerve nucleus. Analysis of histological sections of brainstem of mice and humans stained with Hematoxylin and eosin and Nissl staining allowing morphometric characterization and subsequent comparison offindings in mice and humans. Immunofluorescence for leptin in human brain stem sections. Conclusion: Injection of fluorescein conjugated B subunit portion of cholera toxin (CTB-AF) will allow morphological and functional analysis of motor neurons in the hypoglossal nuclei in mice which are responsible for the innervation of tongue muscles. Studies in humans will allow the translation of technologies between mice and humans. Our preliminary results attest to the feasibility of the project, specifically the success of retrograde neuronal tracing and leptin signaling studies in mice. Successful collaboration between researchers from Johns Hopkins University and Universidade de Sao Paulo has already led to peer-reviewed publications and scientific merit awards. Our collaborative proposal will facilitate cutting-edge research and development of science in Brazil. (AU)

Scientific publications

(9)

(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)

FREIRE, CARLA; PHO, HUY; FONTI, SHANNON; KIM, LENISE; FLEURY-CURADO, THOMAZ; SENNES, LUIZ; POLOTSKY, VSEVOLOD. Intranasal Leptin Prevents Opioid-induced Deaths in Mice. FASEB JOURNAL, v. 35, p. 2-pg., 2021-05-01. (18/08758-3)

FREIRE, CARLA; PHO, HUV; RAMSEV, JACOB D.; ZHAO, YULING; KIM, LENISE J.; BERGER, SLAVA; ANOKYE-DANSO, FREDERICK; SENNES, LUIZ U.; AHIMA, REXFORD S.; BATRAKOVA, ELENA V.; et al. Treatment of Sleep Disordered Breathing with Leptin Loaded Extracellular Vesicles. FASEB JOURNAL, v. 36, p. 1-pg., 2022-01-01. (18/08758-3)

FREIRE, CARLA; PHO, HUY; KIM, LENISE; WANG, XIN; DYAVANAPALLI, JHANSI; DERGACHEVA, OLGA; STREETER, STONE; FLEURY-CURADO, THOMAZ; SENNES, LUIZ; POLOTSKY, VSEVOLOD. Intranasal Leptin Prevents Opioid Induced Respiratory Depression in Obesity. FASEB JOURNAL, v. 34, p. 2-pg., 2020-04-01. (18/08758-3)

FREIRE, CARLA; PHO, HUY; BERGER, SLAVA; FLEURY-CURADO, THOMAZ; SENNES, LUIZ U.; SCHWARTZ, ALAN R.; POLOTSKY, VSEVOLOD Y.. ACTIVATION OF LEPTIN RECEPTOR POSITIVE NEURONS IN THE NUCLEUS OF THE SOLITARY TRACT (NTS) ALLEVIATES SLEEP DISORDERED BREATHING IN OBESE MICE. Sleep, v. 42, p. 1-pg., 2019-04-01. (18/08758-3)

FREIRE, CARLA; PHO, HUY; BEVANS-FONTI, SHANNON; SENNES, LUIZ U.; POLOTSKY, VSEVOLOD Y.. Intranasal leptin improves survival after opioid overdose in a mouse model. JOURNAL OF TRANSLATIONAL MEDICINE, v. 19, n. 1, MAR 31 2021. (18/08758-3)

FREIRE, C.; PHO, H.; FONTI, S.; HOSAMANE, N.; KIM, L.; SENNES, L. U.; POLOTSKY, V. Y.. Intranasal Leptin Reduces Mortality from Opioid Overdose in Mice. American Journal of Respiratory and Critical Care Medicine, v. 203, n. 9, p. 1-pg., 2021-05-01. (18/08758-3)

FREIRE, CARLA; SENNES, LUIZ U.; POLOTSKY, VSEVOLOD Y.. Opioids and obstructive sleep apnea. JOURNAL OF CLINICAL SLEEP MEDICINE, v. 18, n. 2, p. 6-pg., 2022-02-01. (18/08758-3)

FREIRE, CARLA; RAMSEY, JACOB D.; PHO, HUY; KOJIMA, RYO; ZHAO, YULING; KIM, LENISE; ANOKYE-DANSO, FREDERICK; BERGER, SLAVA; AHIMA, REXFORD S.; BATRAKOVA, ELENA V.; et al. Leptin-loaded Extracellular Vesicles Treat Sleep-disordered Breathing in Mice with Obesity. American Journal of Respiratory Cell and Molecular Biology, v. 67, n. 6, p. 4-pg., 2022-12-01. (18/08758-3)

FREIRE, CARLA; PHO, HUY; KIM, LENISE J.; WANG, XIN; DYAVANAPALLI, JHANSI; STREETER, STONE R.; FLEURY-CURADO, THOMAZ; SENNES, LUIZ U.; MENDELOWITZ, DAVID; POLOTSKY, VSEVOLOD Y.. Intranasal Leptin Prevents Opioid-induced Sleep-disordered Breathing in Obese Mice. American Journal of Respiratory Cell and Molecular Biology, v. 63, n. 4, p. 8-pg., 2020-10-01. (18/08758-3)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

LIMA, Carla Freire de Castro. Malnutrition and sarcopenia in cirrhotic patients with and without abdominal hernia. 2021. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.