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Participation of toll-like receptor 9 (TLR9) in prostate dysfunctions of insulin resistance obese mice

Grant number: 16/20592-8
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): June 01, 2017
Effective date (End): May 27, 2018
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Edson Antunes
Grantee:Fabiano Beraldi Calmasini
Supervisor: Robert Clinton Webb
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Augusta University, United States  
Associated to the scholarship:16/01178-6 - Study of prostate smooth muscle hyperreactivity in insulin-resistance obese mice: Role of TLR4., BP.PD


The worldwide incidence of obesity has increased dramatically in the past 25 years, and today is considered one of the major public health problems. Recent clinical studies indicate a strong correlation between obesity and genitourinary tract diseases, such as erectile dysfunction and overactive bladder syndrome. The benign prostatic hyperplasia (BPH), which is characterized by an increase in both physical size (static component) and prostate smooth muscle tone (dynamic component) has been also linked to obesity in humans and animals. Experimental studies demonstrated that prostates from obese rats show increased cell proliferation with consequent prostate overgrowth and hypercontractility, secondary to BPH. Furthermore, obese mice exhibited increases in prostatic levels of NF-kB and gp91phox, p22phox and p47phox protein expression (subunits of NADPH oxidase). A preliminary study in our group showed that high-fat diet (HFD) obese mice exhibit prostate hypercontractility associated with a significant increase (52%) in prostatic reactive oxygen species levels. Recent studies have been shown an important role for Toll-like receptors (TLR), particularly subtype 9 (TLR9), in the exacerbation of the chronic inflammatory condition associated with obesity, however the literature is scarce about the participation of TLR in prostatic disorders. Thus, this project aims to evaluate the role of TLR9 and its downstream signaling pathway in the pathogenesis of obesity-induced prostate dysfunctions. Our hypothesis is that the prostatic dysfunction in obese individuals have in common the activation of TLR9 with consequent increase in intracellular signaling and inflammatory factor production. Specifically, we hypothesize that prostatic TLR9 activation in obese animals leads to the production of pro-inflammatory cytokines and reactive-oxygen species resulting in prostatic hypercontractility and BPH development. If our hypothesis is correct, the pathway components involved in TLR9 activation will be ideal targets for new drugs to reduce prostate complications associated with obesity. (AU)

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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)
CALMASINI, FABIANO B.; MCCARTHY, CAMERON G.; WENCESLAU, CAMILLA F.; PRIVIERO, FERNANDA B. M.; ANTUNES, EDSON; WEBB, R. CLINTON. Toll-like receptor 9 regulates metabolic profile and contributes to obesity-induced benign prostatic hyperplasia in mice. PHARMACOLOGICAL REPORTS, v. 72, n. 1, p. 179-187, . (16/20592-8)
PRIVIERO, FERNANDA; CALMASINI, FABIANO BERALDI; MCCARTHY, CAMERON; WENCESLAU, CAMILLA FERREIRA; ANTUNES, EDSON; WEBB, R. CLINTON. Functional Impairment in the Corpus Cavernosum Related to a High Fat Diet is Prevented in Toll-Like Receptor 9 Mutant Mice. FASEB JOURNAL, v. 32, n. 1, p. 2-pg., . (16/20592-8)
PRIVIERO, FERNANDA; ONUOHA, NINA; CALMASINI, FABIANO BERALDI; OGBI, SAFIA; WEBB, R. CLINTON. NLRP3 Inflammasomes Contribute to the Impaired Bladder Contraction in Male Diabetic Mice. FASEB JOURNAL, v. 33, p. 2-pg., . (16/20592-8)
CALMASINI, FABIANO BERALDI; MCCARTHY, CAMERON G.; WENCESLAU, CAMILLA F.; PRIVIERO, FERNANDA B. M.; ANTUNES, EDSON; WEBB, R. C.. Participation of Toll-like Receptor (TLR) 9 in Obesity-Induced Benign Prostatic Hyperplasia (BPH) in Mice: Implication of Periprostatic Fat. FASEB JOURNAL, v. 32, n. 1, p. 2-pg., . (16/20592-8)
MCCARTHY, CAMERON G.; WENCESLAU, CAMILLA F.; CALMASINI, FABIANO B.; KLEE, NICOLE S.; BRANDS, MICHAEL W.; JOE, BINA; WEBB, R. CLINTON. Reconstitution of autophagy ameliorates vascular function and arterial stiffening in spontaneously hypertensive rats. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 317, n. 5, p. H1013-H1027, . (16/20592-8)
PRIVIERO, FERNANDA; CALMASINI, FABIANO; DELA JUSTINA, VANESSA; WENCESLAU, CAMILLA F.; MCCARTHY, CAMERON G.; WEBB, R. CLINTON. Macrophage-Specific Toll Like Receptor 9 (TLR9) Causes Corpus Cavernosum Dysfunction in Mice Fed a High Fat Diet. Journal of Sexual Medicine, v. 18, n. 4, p. 9-pg., . (16/20592-8)
CALMASINI, FABIANO B.; KLEE, NICOLE; WEBB, R. CLINTON; PRIVIERO, FERNANDA. Impact of Immune System Activation and Vascular Impairment on Male and Female Sexual Dysfunction. SEXUAL MEDICINE REVIEWS, v. 7, n. 4, p. 604-613, . (16/20592-8)

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