$25,000 Award to Professor Robert Semple
We are pleased to announce the second recipient of our 2021 Research Grant.
Dr. Robert Semple will receive a $25,000 grant for the project titled “Human Pluripotent Stem Cells as a Model to Interrogate Pathogenesis and Developmental Origins of CLOVES”
This project will investigate human induced pluripotent stem cells (iPSCs) as a model system to examine the developmental origins of CLOVES, and to test new approaches to treatment. iPSCs are made by “reprogramming” cells from biopsies of healthy adult volunteers. They have the characteristics of true human embryonic cells, including the ability to turn into almost any cell type in the human body under the right conditions. This means that these cells can be used in the lab to examine abnormal development and growth of all the tissues affected in CLOVES syndrome. Crucially, only human cells are involved, which is important as mouse models do not perfectly mimic CLOVES when human mutations are introduced. For this project, genetic “scissors” have already been used to introduce one or two CLOVES syndrome PIK3CA mutations to iPSCs. The effect of these mutations on the ability of cells to make blood vessel and blood cells will first be examined, and then CLOVES will be mimicked by mixing different proportions of unaffected and CLOVES syndrome mutant cells. Analysis will use advanced single cell sequencing techniques to assess the points in development where abnormalities occur, to assess whether the presence of cells with mutations affects the growth of healthy cells, and to assess the effects of drugs on the abnormalities observed. The project will be a collaboration among scientists with expertise in CLOVES, in blood and blood vessel development, and in advanced statistical analysis of single cell sequencing studies.
Dr. Robert Semple
University of Edinburgh Centre for Cardiovascular Science
47 Little France Crescent
Edinburgh, EH16 4TJ, UK
$25,000 Award to Ana Angulo-Urarte
Ana Angulo-Urarte received a $25,000 grant for the project titled “Identifying the molecular impact of PIK3CA variants in PROS towards stratification of patients and personalized medicine.”
This research project will enhance the fundamental understanding of the physiological and molecular insight into PIK3CA-related overgrowth spectrum (PROS) and address fundamental biological questions concerning who (PiK3CA variant) and how (triggered mechanism) activating PIK3CA variants contribute to the development and severity of PROS conditions.
In April 2020, Ana joined the interdisciplinary team of Mariona Graupera to understand from the developmental and molecular point of view the broad presentation of PROS in patients using both patient samples and complex mice models. In February 2021, the group moved to the Josep Carreras Institute where Ana will drive the PROS research line in the lab of Dr. Graupera. Please read Ana’s summary of this project below.
Thanks to the close collaboration between clinicians and researchers, we now know that a series of congenital overgrowth conditions, the so-called PIK3CA-related overgrowth spectrum (PROS), are caused by mutations in the PIK3CA gene. The critical mutations found in PIK3CA are not limited to a specific site but can span almost the entire gene.
With this grant, we want to explore whether different mutations able to activate PIK3CA may have an impact in the type and severity of disorder. It has been found that all PROS patients present, to some extent, the vasculature compartment affected. Therefore, we will select patient endothelial-derived cells, the ones lining the internal surface of blood vessels, as a model of study. In these cells, we will look for common and specific molecular and cellular features triggered by different mutations in PIK3CA.
This study will help to identify new biomarkers of PIK3CA-related signaling activation and, eventually, specific targets that can be used to develop personalized therapies in the future.
$10,000 Award to Dr. Bryan Sisk
We’re pleased to support Dr. Bryan Sisk, Assistant Professor of Pediatric Hematology and Oncology at Bioethics Research Center research study titled “Vascular anomalies communication” (VACOM) with a $10,000 grant. Vascular anomalies are a group of rare disorders that can be disfiguring, painful, and even life-threatening. In our experiences, families affected by vascular anomalies have described multiple barriers to care and communication, such as difficulty accessing care from experts, persistent uncertainty about the diagnosis, and long-term consequences, insufficient information to guide decisions, and the necessity of persistent parental advocacy to ensure the child receives adequate medical care. However, no researchers have explored or categorized the needs or barriers experienced by these families.
We are performing a study that will incorporate interviews and surveys with caregivers and adult patients with vascular anomalies. In this 2-year study, we will learn about care and communication experiences from the patients’ and caregivers’ perspectives. We will also learn how these experiences affect quality of life and wellbeing. We will share our findings with the CLOVES community through interactive webinars at the beginning, middle, and end of the study. We will also share our results with clinicians and researchers who care for patients with vascular anomalies. These findings will be essential to develop future interventions to improve care and communication for these families.
$20,000 Award to Ralitsa Madsen
Dr. Madsen, during her PhD in Professor Robert Semple’s group at Cambridge University, developed the first developmental cell models with PIK3CA-H1047R expression. This discovery has revised the prevailing understanding of how PIK3CA mutations may cause diseases such as PIK3CA Related Overgrowth Spectrum (PROS) and cancer, suggesting that it is not only important to know whether or not a mutation is present, but also its exact dose and thus the strength of PI3K pathway activation.
We’re supporting a project called “The systems biology of activating PIK3CA mutations in mosaic endothelial cell models.” Diseases of human growth and development are often caused by genetic mutations that disrupt critical circuits inside our cells. Analogous to a broken radio, a cell affected by such a mutation no longer “plays the right music”. The PI3K circuit is one of the most commonly disrupted in cancer and developmental growth disorders known as PROS. Its disruption in PROS leads to unabated growth and a range of debilitating challenges. Despite available PI3K inhibitors, treatment of PROS remains limited, in part due to the diversity of cell types that can be affected – each one “playing the wrong tune” in its own unique way. A detailed understanding of these cells, and how to treat them, requires quantitative characterization of the malfunctioning circuit components. In addition, there is a need to understand whether diseased cells may influence, or even reprogram, healthy cells in a mosaic tissue to behave abnormally. This grant will support the engineering of novel cell model systems that enable studies addressing these critical questions.
February of 2019
$30,000 Award to Canaud Lab
We awarded $30,000 to Canaud Lab for their continued work on CLOVES/PROS. This award will be used for the creation of animal models to test PIK3CA inhibitors and to study PIK3CA related overgrowth physiopathology. A note from Dr. Canaud to share with our supporters and community:
“Our group is so proud to be supported by the CLOVES Syndrome community. Thanks to you, we are making rapid and important progress on the understanding of the PIKC3A Related Overgrowth Syndrome physiopathology. We hope to share these results with you very soon. We express our gratitude to all the community.”
$14,000 Award to Boston Children’s Hospital
CLOVES Syndrome Community committed to support a project looking for risk factors predicting common complications in CLOVES, using data from the 127 patients with CLOVES in the Lymphatic Anomalies Registry (www.lymphaticregistry.org).