Where Are Your Donations Going?
The Kelleigh Gustafson Accelerated AVM Research Fund
Partnering with Boston Children's Hospital and Dr. Arin K. Greene, we have established the Kelleigh Gustafson Accelerated Research Fund. Dr. Greene's team has found that the endothelial cells lining the inside of blood vessels in extracranial AVMs have mutations in certain genes. Interestingly, these mutations are also found in multiple types of cancer. The ability to understand the mechanisms for AVM formation and develop drugs against AVM is hampered by the absence of an AVM animal model. The research team supported by the Accelerated AVM Research Fund and led by Dr. Greene, is now focused on creating an animal model of AVM by introducing the most common AVM genetic mutation into the genome of the endothelial cells of a mouse, thereby creating mice that will develop AVMs. Dr. Greene's group will then investigate whether treating AVMs in mice with FDA-approved drugs can prevent AVM formation, AVM growth, and/or shrink AVM size. The establishment of drugs for AVM will have a profound impact on patients' lives. Results from these studies will be translated to clinical trials in humans.
The Kelleigh Gustafson Post-Doctoral AVM Research Fellow
At the Medical College of Wisconsin, we have established/funded the Kelleigh Gustafson Post-Doctoral Research Fellowship. Our research fellow has been on teams researching the importance of cilia in the development of zebra fish and the proteins/genetic mutations involved in AVM growth. Conducting any kind of medical or biological research is complex and expensive. It requires the use of a well-funded and equipped research laboratory, complex lab equipment, reagents, chemicals, and animals. The human component includes institutional managers, administrators, organized committees and processes for human and animal research, as well as researchers [PhD’s, physicians, technologists, cell biologists, etc.] with appropriate training and interest.
Translational research, in which findings generated by a basic science lab can be used to change the medical treatment of patients, is probably the most difficult. This is the type of research that Kelleigh’s Cause has endeavored to support at the Medical College of Wisconsin, in conjunction with Children’s Hospital of Wisconsin. The main leaders in this research have been Patricia Burrows MD, Professor of Radiology, an Interventional radiologist with a long-standing interest in treating children and adults with AVMs, and Ramani Ramchandran, PhD, Professor of Pediatrics and Director of the developmental vascular biology program at the Medical College of Wisconsin. These leaders shared the goals of better understanding vascular malformations and improving the lives of patients with these conditions.
What Type of Research has been Funded by Kelleigh's Cause?
Funding from Kelleigh’s Cause was used to pay for lab supplies to process blood and urine samples taken from patients with vascular malformations who are undergoing stage treatment.
The project was designed in 2013, before current knowledge about the genetic causes of AVM. The goal was to identify proteins produced uniquely by the vascular malformations that could be used to help identify novel treatments or used to monitor the results of treatment. We also hoped that a drug treatment could be developed to target that protein. Human research, even involving minimal risk such as collecting blood and urine patients undergoing necessary procedures, is heavily regulated for the protection of the patients. Every document, including specific consent forms, had to be written, reviewed, revised, and approved. Every year, the project was reviewed and new revisions needed. Once the research began, each sample collection required signed consent from the parents, and assent from the child, and then the consent forms had to be carefully stored. Mass spectrometry [a sophisticated test to sort and quantify thousands of tiny proteins] was carried out and a huge volume of computerized data was obtained. This data then had to be translated and interpreted by researchers at MCW, and, in the end, we did not find consistently elevated levels of specific proteins in the samples taken from AVMs.
Kelleigh’s Cause paid for reagents and the mass spectrometry cost. The thousands of hours of work involved in managing the protocol, obtaining and processing the samples and analyzing the results were donated by Dr's Burrows and Ramchandran, the postdoctoral fellows and other researchers involved, as well as MCW and CHW. Unfortunately, the data did not demonstrate any key proteins that could be used clinically in the management of patients with AVM. The remaining samples are still in storage, available for additional testing.
Funding from Kelleigh’s Cause was used to hire a postdoctoral fellow (Dr. Shahram Eisa-Beygei) and purchase supplies and animals for the research.
Initially, zebrafish embryos with RASA1 mutations were purchased from a commercial source. This mutation is known to be associated with a high frequency of AVM in humans. The zebrafish were bred and treated in ways that enhance the visualization of developing blood vessels. They developed defects in the body and blood vessels consistent with what was expected with RASA1 mutation. However, after many months of waiting for the numbers to increase, genetic screening showed that they did not in fact have the RASA1 mutation!
In order to obtain a suitable animal model, a different technique [CRISPR] was used, under development by a medical student Scott Self who pursued this project as part of his honors in research aspect of the medical summer research program. We hope that by inducing mutation in rasa1 with CRISPR method, we will recapitulate the defects in vasculature that we have already observed.
Funding from Kelleigh’s Cause was used to purchase drugs, animals and lab supplies in order to test the altered zebrafish to different dosages of five different medications that had potential to reverse the defect.
Scott Self, the MCW medical student carrying out this research during his free time, developed a grading system to analyze the fish that were injected with rasa1 morpholino, a technique frequently used in zebrafish to knockdown genes. Rasa1 knockdown fish showed numerous vascular defects, which were evaluated under a special microscope to identify defects.
FDA-approved compounds were tested for toxicity first, and non-toxic doses were used to evaluate which drug and dosage was the most effective in “rescuing” the vascular defect. Scott’s salary [stipend] was paid by MCW, and lab space and equipment was provided by Dr. Ramchandran’s lab at MCW. As part of his Honors in Research aspect of the medical school summer research project, Scott Self is committed to pursuing this project to completion.
Funding from Kelleigh’s Cause was used to hire a postdoctoral fellow, Dr. Shahram Eisa-Beygei and to pay for animals and lab supplies. Lab space and equipment, such as a state-of-the-art confocal microscope, were provided by Dr. Ramchandran, Children’s Hospital of Wisconsin and MCW.
The purpose of this work was to obtain insights into the earliest aspects of blood vessel development and determine the role of a tiny endothelial cell appendage, the cilia, in this development. In a very short period of time, and starting essentially from scratch, Dr. Eisa Beygei was able to develop a zebrafish model to study cilia under various conditions. He found that cilia were involved in the very earliest part of blood vessel formation, when a mass of cells develops a lumen or channel. These findings were completely new and were published rapidly, meriting a cover page illustration and complementary editorial in a prominent research journal. Almost simultaneously, another group working from Europe found that some of the genes known to be causative for AVM are localized on the cilia. So the next steps in this research will be to study the effects of these gene mutations on blood vessel development using the same cilia imaging techniques, as well as to study the integrity of cilia in surgical specimens of human AVMs.
Research Relevant to AVM's
SEEKING ADDITIONAL RESEARCH GRANT APPLICANTS
We are currently seeking additional grant applicants that can help us obtain this ultimate goal of finding a better treatment or cure for AVM. For more information about our research or grant application process, please reach out to us by email at firstname.lastname@example.org