In this second article, the Foundation presents the research of our final four grant awardees. Two of these young research scientists are also recipients of our M. Irené Ferrer Award. Doctor Ferrer was a distinguished scholar who used the cardiac catheter to define the nature of heart disease in the living patient.
Our Foundation is proud of all these immensely talented young scholars, whose research will add considerably to our body of gender-specific knowledge related to heart disease, brain function, hormones and infant microbiomes (the population of bacteria that populate the human gut).
These are our latest awardees, whose work you have made possible through your support of the Foundation.
Elaine Wan, MD, FACC, FAHA, FHRS, Esther Aboodi Assistant Professor of Medicine, Cardiology and Cardiac Electrophysiology, Columbia University, 2017 M. Irené Ferrer Scholar Award Recipient
Understanding and developing novel therapeutic treatments are critical in the fight against heart disease. Dr. Wan’s efforts are focused on atrial fibrillation and heart failure. She has created specialized panoramic lighting which merges light activation and optogenetics in transgenic mice to study how various activation patterns can start or stop arrhythmias. Her work involved collaborating with two other biomedical engineering laboratories and colleagues in the field, Dr. Elisa Konofagou and Dr. Gordana Vunjak-Novakovic.
Dr. Wan notes that “the funds provided by the M. Irené Ferrer Scholar Award have allowed me to purchase four high resolution optical mapping cameras and to build a panoramic optical mapping setup that visualizes cardiac electrical activity of the mouse heart in three dimensions.”
She has reported her findings in a paper entitled “Spatial action potential duration gradients are necessary to sustain persistent Na+ current-induced atrial fibrillation in mice” in which she gratefully acknowledges her award from the Foundation for Gender-Specific Medicine.
Gender differences in right ventricular dysfunction (RVD) have been noted but little explored. RVD is closely associated with a number of diseases such as cardiomyopathy, pulmonary embolism, hypertension and myocardial infarction.
Dr. Tsai’s goal is to shed light on gender differences in the molecular pathophysiology of right ventricular dysfunction (RVD).She hypothesizes that differential dysregulation of cyclic guanosine monophosphate (cGMP) signaling might underlie observed the sex differences in RVD.
To date, she has generated male and female mouse models of RVD, using both wild type mice and novel transgenic mice with cardiac-specific deficiency of soluble guanylyl cyclase. Dr. Tsai states, “We described the progress of RVD and right ventricular failure (RVF) in animals in whom we banded the pulmonary artery.”(This increased the work the right ventricle had to do to expel blood through the narrowed pulmonary artery into the lungs.)
In the process of performing her research, Dr. Tsai has incorporated relatively new echocardiographic methods such as strain imaging for assessing right ventricular (RV) function. Molecular and biochemical studies and their analyses are in progress. Preliminary data have been presented in abstract form at national and international scientific meetings and are being incorporated into an original research manuscript about the molecular biology of RV failure. Doctor Tsai anticipates completion of the analyses of both genders of mouse models this summer, with submission of the original research manuscript for publication this fall.
The grants from the Foundation for Gender-Specific Medicine have been instrumental in securing supplies, crucial apparatus, imaging and monitoring equipment for research animals.
Dr. Mueller first explored the hypothesis that sex/gender is associated with the diversity, structure and composition of the gut microbiome (the bacterial population of the intestine). He examined the differences in infant microbiomes between babies born vaginally (during which they received their mother’s microbiome) and children born by Cesarean section, who did not have this advantage.
The findings have been valuable in preparing for a pilot study on the manual transfer of the mother’s vaginal microbiota to newborns delivered by Cesarean section. Since receiving the Foundation Grant, Dr. Mueller was able to finalize protocols and assemble a study team.
Dr. Mueller reports: “I am happy to report that we just received news from the FDA (as of 3/26/18) that we should be approved to start our trial of the effect of microbiome transfer in newborns in April 2018. Throughout this process, I have been able to present the rationale and protocol for our work at several institutions around the U.S., including at Johns Hopkins University, University of Maryland, Dartmouth College, and just recently the Mayo Clinic.”
As Dr. Mueller prepares the next phase of the pilot study, funds from the Foundation grant will support extraction of DNA and high-throughput sequencing of the first 50 infant stool samples. In addition to examining differences by treatment arm, he will explore whether the effect differs by sex. Dr. Mueller adds, “We will present and publish these findings, and use data from this pilot study of 50 infants to apply for NIH support of a larger (600 to 800 mother-infant clinical trial) to test whether vaginal microbiota transfer can prevent C-Section associated diseases. There is global interest in this research.”
Rosanne Rouf, MD, Assistant Professor of Medicine, John Hopkins University
Progress in understanding the pathogenesis of mitral valve prolapse (MVP) and in developing evidence-based therapeutic strategies to treat it has been frustrated by the lack of animal models of MVP which display strong sexual dimorphism analogous to the situation in humans.
Dr. Rouf discovered that Marfan syndrome (MFS), a systemic connective tissue disorder, exhibits dramatic alterations in mitral valve structure and function that worsen with age. Moreover, female MFS mice have worse mitral valve disease than their male counterparts. Furthermore, therapy with losartan, an angiotensin II type 1 receptor blocker frequently used to manage hypertension, reduces MFS myxomatous mitral valve disease in female mice.
Using the funds provided by the Foundation, Dr. Rouf sought to discover whether angiotensin II signaling is increased in female mitral valves compared with male mitral valves in normal and MFS mice. Her data indicated that expression of the main receptor for angiotensin II was increased in female mitral valve tissue as well as receptors for transforming growth factor beta which is an upstream regulator of angiotensin II signaling. Dr. Rouf stated that “We were also able to optimize our protocols to capture both leaflets of the murine mitral valve, a tissue that is on the order of micrometers in length and width and so thin that it is translucent. High resolution techniques were also developed and by using real-time color-Doppler imaging she was able to view the mitral valve in conscious mice to reliably detect mitral regurgitation, a surrogate phenotype for clinically relevant mitral valve prolapse.”
The next research goal is to test the effect of novel pharmacologic agents that minimize signaling through angiotensin II to test whether such agents can reverse mitral valve disease in the murine model and potentially treat the disorder in humans.
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