PAF Awards $49,953 New Research Grant – Swietach

PAF Awards $49,953 New Research Grant

PI: Pawel Swietach, Professor of Physiology, Department of Physiology, Anatomy & Genetics, University of Oxford, England

“Aberrant protein propionylation and distinct histone marks in propionic acidemia: new disease mechanisms and risk factors for cardiac disease”

The challenge placed on our hearts – to contract and relax in a correct sequence and with adequate strength – is formidable.  The elegant biological solution to this mechanical problem is an organ that pumps millions of liters of blood to support life for many decades.  However, the quality and span of a person’s life is strongly linked to cardiac health.  Thanks to scientific breakthroughs, better treatments are now available for cardiac disease, allowing patients to live longer and happier lives.  Our goal at Oxford University’s British Heart Foundation Centre of Research Excellence is to ensure that scientific progress addresses a wide spectrum of disorders, irrespective of their incidence.

Cardiac problems are common in propionic acidemia (PA).  Sadly, dilated cardiomyopathy and long-QT syndrome are often the cause of childhood death.  In order to treat and prevent these cardiac problems, we must first understand the underlying mechanisms.  Once these processes are described, our aimis to identify targets for drugs or interventions.  We believe that this ambition is achievable thanks to the wealth of knowledge about the heart and the vast repertoire of drugs approved for therapy in various other cardiac conditions.  Many of these drugs could be “repurposed” for PA-associated disorders, giving hope to many families for a timely treatment.

For this PAF-funded project, we have assembled a consortium of scientists who are eager to devote their expertise to studying PA.  My laboratory’s expertise is in cardiac cellular physiology in the context of acid-base disorders. We are joined by Tom Milne who is Associate Professor in Epigenetics at Oxford, Holger Kramer, an expert on proteomics, and Steve Krywawych, principal biochemist at Great Ormond Street Hospital in London. Resources and facilities made available to this project include a mouse model of PA, courtesy of Michael Barry and Lourdes Desviat, methods to characterise cardiac function from the cell to organ level, as well as measurements of changes at the protein and gene level.  This interdisciplinary but focused approach allows us to identify potential targets for PA treatment.  Indeed, our preliminary findings point to one such enzyme, and the aim of this project is to test and validate our hypothesis.

PA is associated with major metabolic changes, and many of these substances are not merely intermediates in a chain of events, but can have strong biological actions that are not always intuitive to predict.  Our project will investigate how the build-up of propionate affects cardiac genes through a chemical reaction that causes DNA scaffolds (called histones) to “open up” genes that should not normally be expressed in a healthy heart.  Many genes will be affected by this, but some are more closely linked to the cardiac disorder.  After identifying these lead genes, we will test the extent to which blocking these could be curative. In parallel, we will investigate if propionate can also react with other targets in the cell, such as proteins underpinning contraction.  Indeed, our work suggests that a promising avenue for research relates to so-called excitation-contraction coupling, a process that converts cardiac electricity to a mechanical response.

We are excited to be part of the PA research family and wish to take this opportunity to invite patients, carers, and supporters to our lab for a visit.

 

Partners in Progress: Families and Scientists Catalyze Research for Rare Diseases

“Partners in Progress:  Families and Scientists Catalyze Research for Rare Diseases”

On Nov. 15, 2017, Baylor College of Medicine and Texas Children’s Hospital hosted a panel discussion as part of theEvenings with Genetics seminar series held at the Children’s Museum of Houston. The topic was “Partners in Progress:  Families and Scientists Catalyze Research for Rare Diseases” and panelists traveled from both coasts and the center of the country. Panelists included Jill Chertow Franks, President, Propionic Acidemia Foundation; Cynthia Le Mons, Executive Director of the National Urea Cycle Disorder Foundation, Tracy Smith Hart, Chief Executive Officer, Osteogenesis Imperfecta Foundation and Brendan Lee, MD, PhD, Robert and Janice McNair Endowed Chair, Professor, Department of Molecular and Human Genetics, Baylor College of Medicine. These family/scientist partnerships are a new and exciting development in the research efforts for those impacted by rare diseases.

The audience of almost 80 people consisted of parent leaders, rare disease foundations, medical students, genetic counseling students, pharmaceutical companies and undergraduate biotech majors. Each panelist discussed the partnerships with rare disease organizations and scientists and their strategies for success in obtaining funding for research from the National Institutes of Health (NIH). In addition, panelists shared how they became involved in the rare disease organization and offered advice for other rare disease organizations as well as researchers with regards to working together to submit requests for funding. Dr. Brendan Lee discussed the positive impact of family/scientist partnerships and that these collaborations highly beneficial for progress in understanding rare disorders and developing effective therapies.

Susan D. Fernbach, RN, BSN

Director of Genetic Outreach

Director of Diversity and Community Engagement

Assistant Professor, Dept. Molecular and Human Genetics

Baylor College of Medicine/Texas Children’s Hospital