da Silva Biosketch

OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 01/31/2026)

BIOGRAPHICAL SKETCH

NAME: Alexandre Alves da Silva

eRA COMMONS USER NAME (credential, e.g., agency login): ASILVA

POSITION TITLE: Assistant Professor

EDUCATION/TRAINING 

Personal Statement

My research focuses on uncovering the molecular/cellular mechanisms of central nervous system (CNS) control of glucose homeostasis and cardiovascular function. Specifically, we are examining the powerful CNS- mediated beneficial effects of the brain melanocortin system pathway on the heart’s ability to maintain good contractile function after myocardial infarction (MI) induced by left descending coronary artery ligation. We are also examining the powerful CNS-mediated antidiabetic actions of the leptin-melanocortin system that are capable of maintaining euglycemia even in the absence of normal beta-cell function. I utilize in vitro and ex vivo techniques including perfused hearts for cardiac metabolic studies and isolated cardiomyocytes for studies examining sarcomere contractility and calcium transients. These techniques are coupled with genetic mouse and rat models for in vivo long-term integrative physiological studies of many metabolic and cardiovascular parameters, including cardiac function, to carry out these studies.

Ongoing and recently completed projects that I would like to highlight:

Active

NIH/NHLBI 1R01HL163076               da Silva (MPI with Dr. do Carmo)                  01/09/2023-12/31/2026 “Cardiac protective mechanisms of melanocortin system activation”

The major goal of this project is to examine the mechanisms by which activation of brain melanocortin 4 receptors protects the heart against progressive heart failure in myocardial infarction.

Role: PI (4.2 calendar)

NIH P20GM104357-Supplement                    (Hall, PI)                                             07/01/2021-04/30/2023

“Cardiorenal and Metabolic Diseases Research Center”

The goal is this project is also to generate key preliminary data for R01 application aiming at determining the consequences of parental obesity on offspring cognitive disorders and cardiometabolic dysfunction, and the potential mechanisms involved.

Role: Supplement Project PI (2.4 calendar)

NIH-NIDDK - R01 DK121411                          (do Carmo, PI)                                     09/19/2019-07/31/2023

“Long-term consequences of parental obesity on development programming of cardiorenal diseases in offspring” The major goal of this project is to investigate the effects of parental obesity on kidney dysfunction in offspring. Role: Investigator (1.8 calendar)

NIH 1R01HL11085-01                                    Chen Y (PI)                                         02/01/2022-01/31/2026

“Mechanism of PD1 on cardiac inflammation resolution during heart failure development”

The major goal of this project is to investigate the role of PD1 on several aspects of inflammation development and resolution in a standard model of heart failure.

Role: Investigator (0.6 calendar)

NIH P20 GM104357                                       Hall JE (PI)                                         07/01/2018 – 04/30/2023

Cardiorenal and Metabolic Diseases Research Center

The long-term goal is to develop the Cardiorenal and Metabolic Diseases Research Center and provide infrastructure for multidisciplinary, diverse group of basic, clinical and population scientists working on the common synergistic theme of obesity, cardiorenal and metabolic diseases and to facilitate their collaborations. Role: Sub-Core Leader, Imaging Core (1.2 calendar)

Completed

NIH P20GM104357                                        da Silva (PI)                                        07/01/2019-06/30/2022

Pilot Grants Program-Center of Biomedical Research Excellence (COBRE) “Obesity, Cardiorenal and Metabolic Disease Center”

Title: “CNS mechanisms of cardiac protection in heart failure.”

The major long-term goal is to generate key preliminary data for R01 application aiming to identify the mechanisms by which activation of the brain leptin-melanocortin system protects against heart failure.

Role: PI (1.2 calendar)

NIH/NHLBI PO1 HL519717                            Hall JE (PI)                                         08/01/2014 - 05/31/2020

"Cardiovascular dynamics and their control"

The major long-term goal of this project is to investigate the central nervous system signaling pathways that mediate the antidiabetic actions of leptin.

Role: Investigator of Project I (1.2 calendar)

JP-15440                                                        da Silva (PI)                                        02/01/15-10/31/2017

CAPES-Brazil

"Protective cardiovascular effects of leptin in type-1 diabetes" Role: PI (4.8 calendar)

 Citations (* corresponding author):

1. Omoto ACM, do Carmo JM, Nelson B, Aitken N, Dai X, Moak S, Flynn E, Wang Z, Mouton AJ, Li X, Hall JE, da Silva AA. Central nervous system actions of leptin improve cardiac function after ischemia-reperfusion: role of sympathetic innervation and sex differences. J Am Heart Assoc 11(21):e027081,
2. Gava FN, da Silva AA*, Dai X, Harmancey R, Ashraf S, Omoto ACM, Salgado MC, Moak SP, Li X, Hall JE, do Carmo JM. Restoration of cardiac function after myocardial infarction by long-term activation of the CNS leptin-melanocortin system. JACC: Basic Transl Sci 6(1):55-70,
3. do Carmo JM, Omoto AC, Dai X, Moak SP, Li X, Wang Z, Mouton A, Hall JE, da Silva AA. Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency and diastolic function early in Am J Physiol Heart Circ Physiol 321(3):H485-H495, 2021.
4. da Silva AA*, Hall JE, Dai X, Wang Z, Salgado MC, do Carmo JM. Chronic antidiabetic actions of leptin: Evidence from parabiosis studies for a CNS-derived circulating antidiabetic factor. Diabetes 70(10):2264-74,
5. da Silva AA*, Pinkerton MA, Spradley FT, Palei AC, Hall JE, do Carmo JM. Chronic CNS-mediated cardiometabolic actions of leptin: potential role of sex differences. Am J Physiol Regul Integr Comp Physiol 320(2):R173-R181, 2021.

Positions, Scientific Appointments, and Honors

Positions and Employment

2001-2006             Instructor, Physiology Department, University of Mississippi Medical Center, Jackson, MS.

2006-2014             Assistant Professor, Physiology Department, Univ. of Mississippi Medical Center

2015-2017             Professor, Physiology Dept., Centro Universitario Barao de Maua, Ribeirao Preto – Brazil

2016-2017             Professor, Physiology Dept., Univ. Estadual de Minas Gerais, Passos – Brazil

2018-Present         Assistant Professor, Physiology Department, Univ. of Mississippi Medical Center, Jackson, MS

Honors, Other Experience and Professional Memberships

2023                      Ad-Hoc grant reviewer, Swiss National Foundation

2022                      Grant reviewer, NIH Therapeutic Develop and Pre-Clinical Studies (TDPS) study section

2022                      Grant reviewer, American Heart Association – Vascular Biology study section

2021-present         Special Emphasis Guest Editor, Frontiers Endocrinology (Lausanne) 2020   Special Emphasis  Guest Editor, Frontiers in Physiology

2019-present         Grant reviewer, UMMC – Mississippi Center for Clinical and Translational Research (MCCTR) 2019-present         Grant reviewer, UMMC – Center for Biomedical Research Excellence (COBRE)

2018                      Fujifilm-VisualSonics Vevo® Travel Award in Cardiac Imaging. Council for High Blood Pressure/Kidney Research, American Heart Association

2017                      Marcos Augusto Award, Centro Universitario Barao de Maua, Ribeirao Preto, SP – Brazil

2016-2017             Member, International Committee Board, Centro Universitario Barao de Maua, Ribeirao Preto,

SP – Brazil

2016-2017             Medical Physiology Course Coordinator, Universidade Estadual de Minas Gerais, Passos, MG – Brazil.

2015-2017             Vice-Chair, Research Nucleus, Centro Universitario Barao de Maua, Ribeirao Preto, SP – Brazil

2015-2017             Medical Physiology Course Coordinator, Centro Universitario Barao de Maua, Ribeirao Preto, SP – Brazil

2015-2017             Member, Medical School Faculty Board, Centro Universitario Barao de Maua, Ribeirao Preto, SP – Brazil

2015-2017             Member, Faculty Search Committee, Centro Universitario Barao de Maua, Ribeirao Preto, SP

– Brazil

2015-2017             Abstract reviewer and examiner, Medical School Research Day, Centro Universitario Barao de Maua, Ribeirao Preto, SP – Brazil

2014                      Abstract reviewer, International Society of Hypertension (ISH) 2013-2014   Grant reviewer, UMMC-IRSP

2012-present         Fellow of the American Heart Association

2012-Present        Member and Associate Editor, BMC-Physiology 2011-2017         Member, Editorial Board of Hypertension

2009-2014             Study Section Grant Reviewer for the American Heart Association

2007                      Excellence in Research Award Bronze Level – University of Mississippi Medical Center

2007-present          Member, Inter-American Society of Hypertension

2005                      New Investigator Award from CV Therapeutics. American Heart Association - Council for High  Blood Pressure Research

2005                      Research Recognition Award / Cardiovascular Section of American Physiological Society, APS

2005-Present          Member, American Heart Association. Council for High Blood Pressure/Kidney Research

2003                      American Heart Association Postdoctoral Fellowship (0325353B)

2003-Present          Member, American Physiological Society

2002                      Young investigator Travel Award of International Society of Hypertension, ISH

1999                      MERCK Young Investigator Award/Latin America – Council for High Blood Pressure.

Research, American Heart Association

1998                      Young investigator Travel Award of International Society of Hypertension, ISH

1997- 2001            Predoctoral Fellowship (FAPESP), Nephrology Division, University of Sao Paulo, Sao Paulo, Brazil.

1995-1996             Undergraduate (Scientific Initiation - CNPq) Fellowship, Dept. of Microbiology, University of Sao Paulo, Sao Paulo, Brazil.

1993-1995       Undergraduate (Scientific Initiation - CNPq) Fellowship, Dept. of Pharmacology, University of Sao Paulo, Sao Paulo, Brazil.

Scientific review service:

Ad hoc reviewer for over 42 peer-reviewed scientific journals: JACC-Heart Failure, Hypertension; Diabetes; Circulation Research; American Journal of Physiology – RICP; PlosOne; Peptides; American Journal of Hypertension; Journal of Molecular Endocrinology; Brain Research Bulletin; European Journal of Internal Medicine; Gender Medicine; Journal of Pharmacological and Toxicological Methods; Experimental Biology and Medicine; Future Medicine; Diabetes & Metabolic Syndrome: Clinical Research & Reviews; Acta Diabetologica; several Frontiers Journals, etc.

Contributions to Science

(Selected from over 84 publications and 8 book chapters)

https://www.ncbi.nlm.nih.gov/myncbi/alexandre.silva.1/bibliography/public/

Mission Statement: My laboratory aims at uncovering the cellular/molecular mechanisms by which activation of the brain leptin-melanocortin system improves metabolic and cardiac function in situations of severe stress (i.e., type-1 diabetes and heart failure) with the ultimate goal of developing better strategies to treat cardiometabolic diseases. This is achieved by generating and sharing novel critical data, animal models and new techniques.

Research Focus: My current research focuses on determining the neural pathways and molecular mechanisms responsible for identifies myocardial transcriptional alterations induced by insulin resistance and hyperinsulinemia and their consequences on cardiac metabolism, structure, and function. The contributions below are listed in chronological order.

Role of the leptin-brain MC4R axis in ameliorating cardiovascular function during metabolic stress:

We demonstrated that activation of the brain leptin-MC4R axis restores cardiovascular function (e.g., heart rate, baroreflex sensitivity, intrinsic heart rate control, and blood pressure) in insulin-deficient diabetic animals. Even more surprinsing, we recently observed that leptin markedly improves heart function in non-diabetic and insulin- deficient diabetic rats with heart failure induced by ligation of the left anterior descending coronary artery. These findings highlight a novel mechanism for an important new effect of leptin mediatied by its action on the CNS.

1. do Carmo JM, Hall JE, da Silva AA. Chronic central leptin infusion restores cardiac sympathetic-vagal balance and baroreflex activity in diabetic rats. Am J Physiol Heart Circ Physiol 295: H1974-81, 2008. PMID:
2. da Silva AA*, do Carmo JM, Wang Z, Hall The brain melanocortin system, sympathetic control and obesity hypertension. Physiology (Bethesda) 29:196-202, 2014. (* corresponding author)
3. da Silva AA*, Gava FN, Lataro, RM, Silva CMA, Salgado Chronic central leptin infusion improves cardiac function in STZ-diabetic rats with heart failure. FASEB J 31:853, 2017.
4. Gava FN, da Silva AA*, Dai X, Harmancey R, Ashraf S, Omoto ACM, Salgado MC, Moak SP, Hall JE, do Carmo JM. Restoration of cardiac function after myocardial infarction by chronic activation of the CNS leptin- melanocortin system. JACC Basic Transl Sci 6(1):55-70, 2021. (* corresponding author)
5. Omoto ACM, do Carmo JM, Nelson B, Aitken N, Dai X, Moak S, Flynn E, Wang Z, Mouton AJ, Li X, Hall JE, da Silva AA. Central nervous system actions of leptin improve cardiac function after ischemia-reperfusion: role of sympathetic innervation and sex differences. J Am Heart Assoc 11(21):e027081, 2022

Impact of parental obesity on developmental origins of obesity and cardiometabolic dysfunction; andimpact of obesity on the brain melanocortin system.

We recently observed that offspring from obese parents develop signs of diastolic dysfunction starting very early in life (i.e., 3 weeks of age). In preliminary studies we also observed that these ealy signs of diastolic dysfunction worsen as the offspring get older. In addition, we found that obesity, which is commonly associated with resistance to many of the metabolic effects of leptin, does not induce resistance to the metabolic and cardiovascualr actions of activating the bain melanocortin system.

1. do Carmo JM, Omoto AC, Dai X, Moak SP, Li X, Wang Z, Mouton A, Hall JE, da Silva AA. Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency and diastolic function early in life. Am J Physiol Heart Circ Physiol 321(3):H485-H495,
2. da Silva AA, Gava FN, Omoto ACM, Moak SP, Dai X, Hall JE, do Carmo JM. Intergenerational inheritance of obesity-induced diastolic dysfunction with preserved ejection fraction. Hypertension 74(suppl 1):A090, 2019 (oral presentation at the AHA/Council for High Blood Pressure)
3. da Silva AA*, Kuo JJ, Tallam, Liu J, Hall JE. Chronic cardiovascular and dietary responses to activation of melanocortin 3/4 receptors in a model of visceral J Hypertens 22:S202, 2004 (* corresponding author)

Role of the leptin-brain MC4R axis in regulating whole body glucose homeostasis:

We demonstrated that activation of the leptin-MC4R axis has powerfull antidiabetic actions that are capable of sustaining euglycemia even in animals that lack normal insulin production due to failure of pancreatic beta cells. We also discovered that contrary to pre-existing concensus that the CNS actions of leptin and MC4R activation of peripheral glucose regularion were mediated via the autonomic nervous system, the antidiabetic effects of the leptin-MC4R axis are independent of changes in autonomic activity or pituitary function.

1. da Silva AA*, Spradley FT, Granger JP, Hall JE, do Carmo JM. Brain-mediated antidiabetic, anorexic, and cardiovascular actions of leptin require melanocortin-4 receptor signaling. J Neurophysiol 113: 2786-91, 2015. PMID: 25717164. (* Corresponding author)
2. da Silva AA*, Freeman JN, Hall JE, do Carmo Control of appetite, blood glucose ad blood pressure during melanocortin-4 activation in normoglycemic and diabetic NPY deficient mice. Am J Physiol Integr Comp Physiol 314: R533-R539, 2017. PMID: 29351428. (* Corresponding author)
3. da Silva AA*, Hall JE, Moak SP, Browning J, Houghton HJ, Micheloni GC, do Carmo JM. Role of autonomic nervous system in chronic CNS-mediated antidiabetic action of Am J Physiol Endocrinol Metab 312:E420- E428, 2016. PIMD: 27923809 (* Corresponding author)
4. da Silva AA*, Hall JE, do Carmo JM. Leptin reverses hyperglycemia and hyperphagia in insulin deficient diabetic rats by pituitary-independent central nervous system PLoS One 30:12:e0184805, 2017. PMID: 29190687. (* Corresponding author)
5. da Silva AA*, do Carmo JM, Hall JE. CNS Regulation of Glucose Homeostasis: Role of the Leptin- Melanocortin System. Curr Diab Rep 20(7):29, 2020. PMID: 32451760. (* Corresponding author)

Role of the central nervous system melanocortin system in long-term control of blood pressure and inmediating leptin’s dietary and metabolic effects:

We demonstrated that the brain melanocortin system plays an important role in long-term regulation of blood pressure and heart rate. For instance, blockade of MC4R markedly increases food intake leading to rapid weight gain and morbid obesity while causing bradycardia and small reductions in blood pressure. In addition, we demonstrated that the long-term effects of leptin to induce hypertension, anorexia and weight loss are completely blocked by pharmacological blockade or genetic disruption of MC4R.

1. da Silva AA*, Kuo JJ, Hall JE. Role of hypothalamic melanocortin 3/4-receptors in mediating chronic cardiovascular, renal, and metabolic actions of leptin. Hypertension 43:1312-7, 2004 (* Corresponding author)
2. da Silva AA*, do Carmo JM, Kanyicska B, Dubinion J, Brandon E, Hall Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats. Hypertension 51(4):884- 90, 2008. (* Corresponding author)
3. do Carmo JM, da Silva AA, Rushing JS, Hall Activation of the central melanocortin system contributes to the increased arterial pressure in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 302(5):R561-7, 2012.
4. da Silva AA*, do Carmo JM, Wang Z, Hall JE. Melanocortin-4 receptors and sympathetic nervous system activation in hypertension. Curr Hypertens Rep 21(6):46, 2019. (* Corresponding author)
5. do Carmo JM, da Silva AA, Gava FN, Moak SP, Dai X, Hall JE. Impact of leptin deficiency compared with neuronal-specific leptin receptor deletion on cardiometabolic Am J Physiol Regul Integr Comp Physiol 317(4):R552-62, 2019. PMID: 31411897
6. da Silva AA*, do Carmo JM, Li X, Wang Z, Mouton AJ, Hall JE. Role of hyperinsulinemia and insulin resistance in hypertension: metabolic syndrome revisited. Can J Cardio 36(5):671-82, 2020. PMID: 32389340. (* Corresponding author)