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POTS Epigenetic Research Study
|Dysautonomia International is partnering with Vanderbilt University and the National Institutes of Health to conduct a research study during the Dysautonomia International 2017 Conference exploring epigenetic changes in norepinephrine transporter protein expression in postural orthostatic tachycardia syndrome (POTS). Dr. Satish Raj, one of the world's top POTS experts, will lead the study, screening for epigenetic abnormalities that may be causing POTS symptoms, and seeking to validate a blood test that could be used to screen for these abnormalities in clinical settings.
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Since 2014, Dysautonomia International has invited researchers to conduct ground-breaking POTS research projects at our Annual Conference in Washington, DC. Participation in these studies is completely voluntary for conference guests.
The 2017 Conference study will be led by Dysautonomia International Medical Advisory Board member, Satish Raj, MD, MSCI. Dr. Raj is an Associate Professor of Cardiac Sciences at the University of Calgary and an Adjunct Associate Professor of Medicine at Vanderbilt University. "With this study, we are seeking to confirm the epigenetic findings of Professor Murray Esler and colleagues at the Baker IDI Heart & Diabetes Institute in a larger group of POTS patients, and we seek to validate an easier method of screening for this epigenetic abnormality using a blood test, rather than the current approach, a vein biopsy, which is not available outside of a few large research centers," explains Dr. Raj.
What is NET?
Norepinephrine transporter protein (NET) is a pump that helps the nerves recycle norepinephrine, a catecholamine that transmits messages between nerves. Norepinephrine is released by the nerve terminal into the synapse (the space between the nerve). Some of the norepinephrine is taken up by the alpha and beta-adrenergic receptors on the second nerve. Some of the norepinephrine is recycled back up into the first nerve by the NET protein pump. The remaining norepinephrine leaks into the blood stream. Researchers believe that some POTS patients have a NET deficiency that makes them leak too much norepinephrine into their bloodstream, resulting in POTS symptoms.
Image Credit: Schroeder C, Jordan J. Norepinephrine transporter function and human cardiovascular
disease. Am J Physiol Heart Circ Physiol. 2012; 303 (11): H1273-H1282.
History of NET Research in POTS
In 2000, Vanderbilt researchers discovered a mutation on the SLC6A2 gene, which encodes the norepinephrine transporter (NET) protein in a POTS patient. This mutation was associated with a deficiency of NET protein, an excess of norepinerphrine in the blood, and symptoms of POTS. The researchers thought this mutation might be causing POTS in others too. However, after testing many other POTS patients for this mutation over a period of years, this NET mutation was never found in another family.
In 2008, researchers from the Baker IDI Heart & Diabetes Research Institute in Melbourne, Australia, led by Professor Murray Esler, published a paper looking at NET protein expression in POTS patients. Using vein biopsies which are richly innervated with sympathetic neurons, the Baker IDI team found that some POTS patients had reduced or almost no NET protein in their sympathetic nerves, even though their NET gene did not have a mutation. This suggested that the problem was not the gene, but the way the gene is transcribed to make the NET protein.
In 2012, the Baker IDI group did a a larger study seeking to identify the NET transcription problem. Studying the sympathetic nerves in vein biopsies, they found several epigenetic modifications impacting the transcription process that caused functional NET deficiency in some POTS patients.
Image Credit: Bayles R et al. Arterioscler Thromb Vasc Biol 2012;32:1910-1916.
In 2017, the Baker IDI group proposed studies of a cancer drug that may target the epigenetic mechanism seen in some POTS patients. As a part of this work, they are tracking NET expression using an a blood test for the messenger RNA (mRNA) that codes for NET. This mRNA is harvested from whole blood, and does not require an invasive tissue biopsy.
The use of a whole blood mRNA assay for assessment of NET expression offers multiple advantages over vein biopsy, including ease of collection and less trauma to the patient. To date, it has not been shown that NET mRNA blood tests correlate with NET function.
About the 2017 Conference Study
Dysautonomia International invited researchers to submit proposals to conduct a POTS research study at our 2017 Annual Conference. We received numerous proposals for high-quality research. This project was selected after review of all proposals by our Medical Advisory Board, Patient Advisory Board, and independent physician and patient experts who aren't on our board. To maintain independence of the review process, applicants and reviewers affiliated with the applicants' institution were not part of the review process.
Vanderbilt University researchers will invite 150 POTS patients and healthy controls, ages 13-80 years, to volunteer for a study comparing their blood and urine catecholamine levels to their whole blood mRNA, and collecting other information. If we can show that whole blood mRNA assays reliably assess NET expression and that this correlates with NET function (catecholamine levels), it is our hope that this may lead to an mRNA blood test that would eventually be available for clinical use in evaluating POTS patients.
The study will only be open to individuals who are registered for Dysautonomia International's 2017 Conference. The study will occur on Saturday and Sunday during the conference, and will take about 30-45 minutes for study volunteers to complete.
The study will include:
- -an online survey
- -a detailed medical history
- -a physical exam that includes orthostatic vitals and a joint hypermobility assessment
- -blood tests (less than 2 teaspoons of blood) screening for supine and upright plasma catecholamines, NET mRNA, and blood to be stored for future assays of hormones, peptides and cytokines
- -a morning urine sample
We are hosting a webinar with Dr. Raj on June 21, 2017 from 7pm-8pm Eastern to provide more information on the study for those who may be interested in enrolling, and those who may want to learn more about the relevance of NET in POTS research in general. Registered conference guests will also receive an email with information about the study before the conference, and the researchers will be available to answer questions for interested study volunteers on Friday evening during the conference.
How will the donated funds be used?
The research study will cost approximately $75,000 to complete. Dysautonomia International will fund this project through its POTS Research Fund. All donations to the POTS Research Fund go directly to support research. If we raise more than $75,000 or the study ends up costing less than $75,000, any unused funds will be kept in Dysautonomia International's POTS Research Fund and used to fund additional POTS research.
Study expenses include blood draw kits, test tubes, 150 mRNA blood tests, 150 cytokine blood tests, 300 catecholamine blood tests, urine test kits, 150 urine tests for catecholamines, printed materials and labels, shipping fees for specimens and equipment, institutional overhead and institutional (ethics) review board fees charged by the university, travel and lodging to get the researchers to the conference, and covering the staff time needed to process the samples and analyze the data. Some of the Vanderbilt research staff, along with noted catecholamine researcher Dr. David Goldstein and colleagues at the National Institute of Neurological Disorders and Stroke, have volunteered their time and talents to make this project possible, which we are very grateful for.
Can I donate by check?
Yes, please print out this form and mail it in with your check to the address listed on the form. Please note "POTS Research Fund - NET" in the memo line on your check.
Can I host an online fundraiser to support this research?
You can use Crowdrise or to set up an online fundraiser to benefit Dysautonomia International's POTS Research Fund. Mention that your fundraiser is for this project when you set up the fundraising page, and we will allocate all of the funds you raise to this project.
Can I host a live fundraiser to support this research?
Yes, there are fundraising ideas and educational materials available for download on our website.
Please feel free to contact our Director of Events & Community Affairs, Kirsten Slowey, at firstname.lastname@example.org with any Crowdrise, fundraising, or event planning questions. We are here to help you maximize your impact!
All donors will receive a receipt. Dysautonomia International is a 501(c)(3) non-profit and all donations are tax-deductible to the maximum extent permitted by law.