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Dr. Shehadeh’s laboratory is investigating the molecular mechanisms by which microRNAs regulate atherogenesis and stem cell differentiation. In parallel with the mechanistic studies, the Shehadeh lab is actively engaged in developing a targeted delivery method for microRNAs using aptamer technology. Dr. Shehadeh’s expertise in computational biology and data mining allows her to compile masses of genomic datasets to identify candidate genes and microRNAs with potential therapeutic functions. Her research has identified Osteopontin as a major regulator of heart failure and Alport pathologies. In addition to animal models, she uses translational tools such as AAV9 gene therapy, RNA aptamers, monoclonal antibodies, and patient-derived iPSC differentiation to reverse heart failure and prevent cholesterol influx in renal tubules.​

Research Interests


Alport Syndrome

Alport Syndrome is a hereditary rare kidney disease characterized by kidney dysfunction, high blood pressure, hearing loss, and vision deficiency. Sadly, the available treatments nowadays do not prevent the disease from progressing into end stage renal failure. Therefore, Alport patients have no options but to go on dialysis and eventually wait for kidney transplant in order to survive. Our research in the Alport mouse has uncovered mechanisms for accumulated cholesterol and impaired mitochondrial function in the renal tubules. By using genetic deletion of the culprit gene (Osteopontin), we were able to extend the lifespan of the Alport mouse as well as improve its kidney, cardiac, vascular, vision and hearing function. The goal of our work is to present a new treatment for Alport patients.

Our clinical collaborators include:

Dr. Michael Freundlich, MD, Pediatric Nephrologist

Dr. Chryso P Katsoufis, MD, Pediatric Nephrologist

Dr. Bradley Goldstein, MD/PhD, Otolaryngologitst

Dr. Stefania Gongalves, MD, Otolaryngologist

Dr. Alfonso Sabater, MD, Ophtalmologist

Our expert collaborators include:

Dr. Zane Zeier, PhD,  iPSC Researcher

Heart Failure with Preserved Ejection Fraction (HFpEF)

Cardiovascular disease is the leading cause of death worldwide. Heart Failure with Preserved Ejection Fraction (HFpEF) is a type of heart failure that accounts for more than 50% of all heart failure cases. While the conventional form of heart failure, Heart Failure with reduced Ejection Fraction (called HFrEF), is featured by the systolic dysfunction of the heart (failure of the heart to pump out the blood), HFpEF is about diastolic dysfunction (failure of the heart to relax properly after each beat). In addition to diastolic dysfunction, HFpEF syndrome has multiple features including but not limited to, hypertension, myocardial stiffness, hypertrophy and fibrosis. To date, there is no treatment for HFpEF and even the conventional medications that work for HFrEF patients are ineffective for HFpEF treatment. Moreover, the field lacks a definitive animal model for HFpEF that serves as a reason for the slow rate of drug discovery for HFpEF and failure of many clinical trials. Our extensive studies on cardiac phenotype of the mouse model of a rare kidney disease named Alport syndrome mouse model, has led us to introduce this mouse as a novel experimental model for HFpEF.  Among other cardiac pathologies, our model has another important commonality with HFpEF: increased levels of Osteopontin (OPN) in plasma. OPN is a pro-fibrotic matricellular protein and its levels in the plasma of HFpEF patients are directly correlated with the outcome of the disease. Therefore, we have evaluated the role of blocking OPN in this model and obtained interesting result. Our findings show that the lack of OPN is cardioprotective in this model potentially through improving myocardial mitochondrial respiration via upregulation of a mitochondrial protein called OGDHL (Oxoglutarate Dehydrogenase-Like). Our strategy to treat HFpEF is by blocking circulating OPN protein or by OGDHL gene therapy to the heart. Our work may provide new therapies for HFpEF patients. 

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Cardiac Regeneration

Cardiovascular disease remains the leading cause of death worldwide and in the USA. Our studies focus on understanding the process of cardiac regeneration using different treatments in animal models of myocardial infarction (heart attack model) and transverse aortic constriction (hypertrophy model). We use the mosaic analyses with double markers (MADM) model that allows to track dividing adult and neonatal cardiac myocytes. Finding methods to make an adult cardiac myocyte divide into two daughter functional cells is an unmet clinical need for heart attack patients who lose viable cardiac cells. The goal is to provide heart attack patients with new inducers of cardiac regeneration.     

Our expert collaborators include:

Dr. Keith Webster, PhD. Cardiac and Vascular Expert

Dr. Konstantinos Chatzistergos, PhD.iPS-Cardiomyocyte Expert


Atherosclerosis is an inflammatory disease initiating with endothelial dysfunction in arterial wall followed by fatty streak formation and development into atheroma and characteristic plaques. Atherosclerosis is the main cause of cardiovascular disease. However, despite availability of conventional therapeutic agents targeting cholesterol homeostasis and inflammatory response in vessel walls, more than 1 in 3 American adults has at least one type of cardiovascular disease. Therefore, further insights into the pathophysiology of atherosclerosis and introducing novel therapeutic targets represent an unmet clinical need. It is shown that OPN is overexpressed in the human atherosclerotic plaque. Also, it is shown that knocking out OPN reduces atherosclerotic plaque burden in the aorta in the apolipoprotein-E deficient (APOE-/-) mouse model of atherosclerosis. Interestingly, this improvement only happens in female mice while male mice do not achieve any benefit with OPN deficiency. We are investigating the role of OPN deficiency in the cardiac dysfunction in these mice along with its detailed mechanisms of action. In addition, we are investigating the hearing deficit related in these atherogenic mice. Hearing loss is one of the non-cardiac pathologies that atherosclerotic patients may suffer from. Our goal is to provide novel therapies to prevent or reverse blockage of arteries in atherosclerotic patients.

Our expert collaborators include:

Dr. Roberto Vazquez, PhD, Vascular Biologist

Cholesterol Influx

Many diseases in today’s society result in dysregulation of proteins leading to increased cholesterol influx and therefore cholesterol toxicity. We are performing studies on cholesterol influx in tissues from various disease models including heart failure, atherosclerosis, and kidney disease. Understanding changes in protein expression and related effects on cholesterol influx will lead us to innovative therapies for heart and kidney patients.

Our expert collaborators include:

Dr. Armando Mendez, PhD, Lipids Researcher

Duchenne Muscular Dystrophy 

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder characterized by progressive muscle degeneration and weakness. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact.  Symptoms of DMD start from early childhood, usually between ages three and five. The disease primarily affects males, but in rare cases females. Despite advancements in the research and trials, there is no treatment for DMD. Our lab has an active project to investigate the role of Osteopontin (OPN) in the cardiac and muscular pathophysiology in a mouse model of DMD (mdx mouse). Using translational approaches, we may provide novel therapies for Duchenne patients.

Our expert collaborators include:

Dr. Justin Percival, PhD, Duchenne Researcher

Our clinical collaborators include:

Dr. Sakir Gultekin, MD, Neuromuscular Pathologist

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