Current Trainees

 
Fatima El Adili, MD
(July 2019-Present)
Mentor: Andrea Bujor, MD, PhD

Trainees Research Project and Progress

SSc is an autoimmune connective tissue disease in which endothelial dysfunction, inflammation and fibroblast activation lead to skin and internal organ fibrosis. This disease carries the highest mortality rate amongst autoimmune diseases, and is frequently complicated by heart involvement. The goal of Dr. Adili’s research project is to determine the role of monocytes and macrophages in SSc cardiomyopathy (CMP). We have recently discovered that the transcription factor Fli1 is expressed at low levels in SSc monocytes. We have deleted Fli1 via siRNA in human Mo/Mø, and via Cre mediated recombination in LysMCre/Fli1fl/fl mouse cells. Our preliminary data shows that deletion of Fli1 in Mo/Mø via si-RNA, or via Cre-mediated recombination using LysMCre mice (LysMCre/Fli1fl/fl), results in upregulation of several pro-inflammatory and chemotactic genes.

To expand on these studies we will leverage an existing repository of human heart tissue from SSc patients and controls to validate the findings from LysMCre/Fli1fl/fl mice. The LysMCre/Fli1fl/fl mice have enhanced inflammatory infiltrates, heart fibrosis and diastolic dysfunction; SSc-CMP will have Mø with low Fli1 that will display a similar phenotype to the LysMCre/Fli1fl/fl heart Mø. This project is innovative because it tests the novel concept that low Fli1 in SSc-Mo/Mø contributes to organ fibrosis, via a comprehensive approach using human samples and conditional mutagenesis and lineage tracing in mice. The significance of this work lies in the potential to identify Fli1 as a new therapeutic target for SSc CMP, which has no current treatment options and high mortality.

Conference Presentations

Poster presentation at Evans Days Boston University October 18 2019, Boston, MA.

Publications

Andreea Bujor, Fatima El adili; Arshi Parvez Olivia Heutlinger; Giuseppina Farina, Flora Sam. Periostin is increased in scleroderma cardiomyopathy. Arthritis Research and Therapy, 2019 November ARRT-D-19-00749 – Under review

Trainee designed and conducted experiments, analyzed data, and reviewed the final manuscript.


Jordan Chambers, PhD 
(July 2020 – Present) 
Mentor: Wilson Colucci, MD
Trainees Research Project and Progress

The prevalence of heart failure continues to increase and is expected to rise to 8 million people in the U.S by 2030. Heart failure patients face poor prognoses, including reduced quality of life, hospitalization, and premature death. Multiple clinical trials have shown that antidiabetic therapy Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors are cardioprotective in patients with diabetes, and recently have shown efficacy in improving outcomes in heart failure patients regardless of diabetic status. However, the mechanism(s) of protection remain elusive. The goal of my research project is to understand the mechanism by which SGLT2 inhibitors are cardioprotective in non-diabetics. Our laboratory previously showed that SGLT2 inhibitors prevent cardiac and mitochondrial dysfunction in mice with diet-induced obesity and metabolic syndrome. However, since these mice become diabetic it is unclear if the benefit is due to a cardiac-specific drug target or a consequence of diabetes prevention. To understand how SGLT2 inhibitors protect the heart, we will treat non-diabetic mice that develop dilated cardiomyopathy due to cardiac myocyte-specific over-expression of Gq with the SGLT2 inhibitor ertugliflozin. We will determine the effects of ertugliflozin on cardiac structure, function, and mitochondrial energetics in the Gq hearts, and perform proteomic and gene profile analyses to gain insight into ertugliflozin-mediated cardioprotection. In addition, we will harmonize the omics data generated from this project with samples from our previous study in diabetic mice, enabling assessment of the metabolic effects of SGLT2 inhibition in diabetic vs. non-diabetic hearts. We aim to identify a shared mechanism of action that is independent of glycemia. As the benefits of SGLT2 inhibition in patients with underlying cardiovascular disease and heart failure with or without diabetes were unexpected and the target of action is unknown, these studies have the potential to uncover mechanisms underpinning disease progression and discover new therapeutic avenues in heart failure.


 

Parul Chaudhary, MBBS, PhD
(July 2019 – Present)
Mentor: Richard D. Wainford, PhD

Trainees Research Project and Progress

Over 90% of US adults consume excess dietary salt exceeding 3.4g/day. High salt intake impacts central sympathetic outflow to the kidneys which modulates renal sodium excretion (natriuresis) and blood pressure (BP) regulation. This, in conjunction with the salt sensitivity of BP, which is estimated to exist in 50% of hypertensive individuals, can lead to salt-sensitive hypertension. The goal of my research is to understand the mechanisms underlying the pathophysiology of salt-sensitive hypertension. In hypertensive salt-sensitive and normotensive salt-resistant rat models using central drug infusion, brain microinjection, immunohistochemistry, in-situ hybridization and retrograde neuronal tracing techniques we are investigating the impact of PVN Gαi2 protein on 1) neuronal activation in the PVN of the hypothalamus in response to acute and chronic sodium challenges, and 2) temporal changes in central inflammation and microglial activation in the PVN in response to chronic high salt intake. These result will help elucidate the role of PVN Gαi2 proteins in the neural control of BP and sympathoexcitatory mediated central inflammation in salt-sensitive hypertension. We have a manuscript in preparation detailing the cellular phenotype of Gαi2 expressing neurons in the PVN and have published and initial manuscript detailing the role of PVN Gαi2 proteins in mediating inflammation in the PVN during high salt intake.

Additionally, using human clinical plasma samples from patients in which are able to identify salt sensitive versus salt resistant subjects from the DASH-2 Sodium trial (obtained via the NIH BioLINCC resource), we have conducted an assessment of the impact of urinary sodium to potassium ratios with both hypertension and the salt sensitivity of blood pressure and we are currently conducting metabolomic and lipidomic profiling of these same samples. These results may provide potential biomarkers or a “physiological signature” that can help predict the salt sensitivity of BP in human subjects meeting an unmet clinical need.

Oral Conference Presentations

Increased Urinary Potassium Excretion Does Not Associate With Reduced Systolic Blood Pressure in the Dietary Approaches to Stop Hypertension Sodium Trial. American Heart Association Hypertension Council Hypertension Sessions, September 7 2019, New Orleans, LA.

Reduced Urinary Sodium to Potassium Excretion Ratio Does Not Associate With Reduced

Systolic Blood Pressure in Dietary Approaches to Stop Hypertension Sodium Trial, Evans Department of Medicine Research Days, October 18 2019

Publications

Moreira, Jesse D., Parul Chaudhary, Alissa A. Frame, Franco Puleo, Kayla M. Nist, Eric A. Abkin, Tara L. Moore, Jonique C. George, Richard D. Wainford. “Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein‐dependent, salt‐sensitive hypertension.” Experimental Physiology 2019 104:1892-1910

Trainee designed and conducted experiments, analyzed data, and reviewed the final manuscript.

Parul Chaudhary, Richard D. Wainford. “Association of urinary sodium and potassium excretion with systolic blood pressure in The Dietary Approaches To Stop Hypertension Sodium Trial.” Journal of Human Hypertension – Under review

Trainee designed and conducted experiments, analyzed data, drafted the paper and reviewed the final manuscript.

Career Development Activities

Scientific Writing Course. Department of Anatomy and Neurobiology, Boston University School of medicine, MA.


Beatriz Ferran Perez, PhD
Redox therapy approaches to improve ischemic limb vascularization
(July-2018 to Present)
Mentor: Reiko Matsui, MD

Many diseases are associated with increased levels of reactive oxygen and nitrogen species, however it is demonstrated that certain levels of oxidants are necessary to promote ischemic angiogenesis. Oxidants transduce angiogenic signaling by post-translational protein thiol modifications. The reaction of protein thiols with cellular glutathione (GSH) renders stable protein-GSH adducts (S-glutathionylation), which are able to alter the protein function. Protein-GSH adducts are reversed by glutaredoxin-1 (Glrx), a cytosolic enzyme that can inhibit angiogenesis by modulating several proteins including HIF-1a. We found that Glrx inhibition promotes angiogenesis via HIF-1α stabilization.

My work is focused on redox-regulation of ischemic vascularization related with aging and type 2 diabetes. Diabetic patients have a worse blood flow recovery in response to ischemia comparing with non-diabetic subjects. Since Glrx expression regulates the ischemia-induced angiogenic responses, my research interest is to find out the molecular mechanisms by which modulating Glrx activity/expression in the skeletal muscle may improve vascular recovery after hindlimb ischemia, and to propose an effective therapy. To achieve this goal, my main objectives are A) generate skeletal muscle-specific Glrx KO mice by using the Cre-Lox system and by adeno-associated virus (AAV) injection; B) contribute to establish an AAV production and purification method for in vivo studies; and C) as a therapeutic approach, apply AAV-mediated Glrx inhibition to poor vascularization models like diabetic mice and middle-age female mice.

Work progress

A) The colony of muscle-specific Glrx KO mice is already growing and I expect to have the first animal cohort in three months.

B) I contributed to optimize an affordable protocol for producing and purifying AAV in our laboratory, resulted in a manuscript submitted to Scientific Reports, now in the revision process. Tests of the viral suspensions indicated that AAV particles can be used to inhibit Glrx expression in vivo and in vitro. I am working now in the design of the viral DNA to decrease the inflammation caused by the AAV intramuscular injection.

C) I performed pilot experiments inducing hindlimb ischemia in middle-age mice and confirmed that females show worse blood flow recovery than males. Also, I am working on the method to detect Glrx target proteins in skeletal muscle samples by immunoprecipitation with anti-GSH antibodies.

Presentations

  • Poster presentation in the Evans Research Day. October 11, 2018 (Boston University School of Medicine, Boston)
  • Poster presentation in the 25th Annual Conference of the Society for Redox Biology and Medicine (SfRBM). November 14-17, 2018 (Chicago)
  • Work-in-Progress presentation in the WCVI Seminar Series. January 29th, 2019.

Workshop attendance

Pre-meeting workshop “Oxidative Stress and Signaling: Methods, Mechanisms, and Therapeutics”. November 14th, 2018 (Chicago), at the 25th SfRBM Annual Conference.

Publications

  • Weinberg EO, Ferran B, Tsukahara Y, Hatch MMS, Han J, Murdoch CE, Matsui R. “IL-33 induction and signaling are controlled by glutaredoxin-1 in mouse macrophages.” PLoS One. 2019 Jan 25;14(1):e0210827. (PMID: 30682073)
  • Toyokazu Kimura, Beatriz Ferran, Yuko Tsukahara, Qifan Shang, Suveer Desai, Ivan Luptak, David Richard Pimentel, Takeshi Adachi, Yasuo Ido, Reiko Matsui, Markus Bachschmid. “Production of adeno-associated virus vectors for in vitro and in vivo applications”. Manuscript in revision, submitted to Scientific Reports.

Sana Majid, MD
Determining Cardiovascular Injury due to the Use of Novel Tobacco Products
(July 2018 – Present)
Mentor: Naomi M. Hamburg, MD, MS

Electronic cigarettes (e-cigarettes) are marketed as safer alternatives to combustible tobacco products; however, whether e-cigarettes are a harm reduction tool with reduced cardiovascular (CV) toxicity is unknown. Dr. Majid seeks to identify e-cigarette product characteristics associated with CV injury. Specifically, Dr. Majid will evaluate the effects of Juul, the top selling e-cigarette in the US, on endothelial cell phenotype. She hypothesizes that Juul e-liquids will induce endothelial cell toxicity and that toxicity will vary based on the flavoring additives and nicotine levels. In order to test this hypothesis, she will evaluate the effects of available e-liquids at varying concentrations on cellular viability, nitric oxide production, and oxidative stress in commercially available endothelial cells. She has learned how to perform the assays and will start cell exposures in the coming weeks. Dr. Majid has additional work evaluating the relations of plasma lipids with e-cigarette use in the Cardiovascular Injury due to Tobacco Use (CITU) cohort. She hypothesizes that specific volatile organic compounds may mediate the association of alterations in plasma lipids associated with e-cigarette use. She has written the analytic plan and has begun the analyses. Through her efforts, Dr. Majid will identify e-cigarette product characteristics associated with cardiovascular toxicity. Her work will lend additional support for regulations on product characteristics associated with cardiovascular injury such as setting permissible limits on flavoring additives.

Fellowships

AHA Tobacco Regulation and Addiction Center (A-TRAC) 2.0 Fellowship (2018-2020)

Meeting Attendance

American Heart Association (AHA) Scientific Sessions 2018, Chicago, IL (November 10-12)

Poster presentations

  1. Majid, J. L. Fetterman, R. J. Keith, R. M. Weisbrod, M. Holbrook, M. M. Stathos, R. Breton-Romero, R. Bastin, B. Feng, R. M. Robertson, A. Bhatnagar, N. M. Hamburg. The Impact of Combustible and Electronic Cigarette Use on Vascular Health: An Observational Study. Boston University Evans Department of Medicine Research Days (October 11).

Coursework

Introduction to Statistical Computing – Boston University, Boston, MA (Fall 2018)