This application is submitted in response to the PA-23-189 Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed). The parent grant is ‘Leptin signaling in the carotid body: mechanisms and consequences’, R01HL133100-7, 04/01/2023 – 03/31/2025 with contact PI Vsevolod Y Polotsky, MD, PhD. Obesity is a major health problem leading to high cardiovascular morbidity and mortality Main complications of obesity are hypertension and sleep disordered breathing (SDB), which greatly contribute to obesity-related morbidity and mortality. Our parent grant is focused on mechanisms by which obesity acts on the carotid body (CB), a key sensor of hypoxia and multiple metabolic parameters, to cause hypertension and SDB. In our parent grant we have shown that an adipocyte produced hormone leptin acts on the long isoform of leptin receptor (LEPRb) in the CB glomus (Type I) cells to increase carotid sinus nerve (CSN) activity leading to hypertension. LEPRb signaling in the CB causes transcriptional and post-transcriptional activation of TRPM7, which is responsible for both respiratory and cardiovascular effects of leptin in CB. However, leptin may act on the CB via alternative pathways. Leptin upregulates pro-opiomelanocortin (POMC), which is a pre-hormone post-transcriptionally processed into several peptides, including α-melanocyte stimulating hormone (α-MSH), a ligand for the melanocortin 4 receptor (MC4R). MC4R deficiency prevents the development of hypertension in obesity. MC4R has been implicated in the developing of hypertension in SDB Our Preliminary Data show that CIH leads to a striking increase in Mc4r expression in CB. Of note, Trpm7 knockdown in the CB appeared to attenuate the effect of IH on Mc4r expression, which suggests that MC4R is downstream of leptin-TRPM7 signaling. However, the role of CB MC4R in obesity and SDB related hypertension is unknown. The overarching hypothesis of this proposal is that, DIO and SDB act via MC4R in the CB to increase carotid sinus nerve (CSN) activity and hypoxic chemoreflex leading to hypertension and SDB, all of which can be attenuated by Mc4r shRNA administered to the CB. Specific Aim 1 will examine the role of MC4R in CB in DIO- and CIH- induced hypertension and potential implications for therapy. We propose that DIO and CIH increase MC4R expression in CB, carotid sinus nerve (CSN) and sympathetic nerve (SNS) activity and blood pressure, which will be attenuated by Mc4r shRNA applied to CB. Specific Aim 2 will examine the role of MC4R in CB in DIO-induced SDB and potential implications for therapy. We propose that DIO increases MC4R signaling in CB, which augments chemoreflex, destabilizes breathing and exacerbates SDB, and that Mc4r shRNA applied to CB will decrease hypoxic chemoreflex and attenuate SDB. The Candidate, Dr. Mateus Amorim will work on this proposal paving a way to his future career as an independent investigator.