2015 Cure HHT Young Research Scholar Awards
Cure HHT received twenty-five applications for five $30,000 grants. The research applications were outstanding! The research review committee scored each application and presented their recommendations to the Board of Directors. The Cure HHT Board of Directors, upon the recommendation of the Research Review Committee, chose to fund the 5 top ranked studies. However, during this process a very generous donor came forward; allowing us to raise an additional $30,000 to fund the work of another scientist. There are several more research applications worthy of funding. If you are able to help us fund another grant, please contact [email protected].
High-Content Deep-Phenotypic Screening of Existing Drugs for the Treatment of HHT
Chadwick Davis, PhD, is a Post Doctoral Fellow at Recursion Pharmaceuticals working under the direction of Dr. Dean Li, Professor of Medicine, at the University of Utah. Recursion Pharmaceuticals models loss of function genetic diseases, such as HHT, utilizing high-content cellular imaging and advanced machine learning software that can differentiate between normal and diseased cells. A high-throughput drug screening method identifies repurposed drugs that revert the disease model back to a healthy state. Dr. Davis will utilize this system to discover a known drug with the potential to be repositioned to successfully treat HHT. This study will aim to (1) characterize ENG, ACVRL1, and SMAD4 deficient cell lines using RNAi and (2) identify known drugs that fully or partially ameliorate the HHT phenoprint. Dr. Davis will (a) screen at least 2,727 known drugs and bioactive compounds against the phenoprints identified in Aim 1 and (b) evaluate and prioritize all hits for scientific and medical potential. Dr. Davis expects to find a minimum of one known bioactive compound that fully or partially reverses the phenoprint and can be repurposed for the treatment of HHT.
Endoglin Regulates Biology and Signal Transduction in Vascular Smooth Muscle Cells
Hongyu Tian, PhD, is a Post Doctoral Research Associate at Duke University working under the direction of Dr. Gerard Blobe, Professor of Medicine and Professor of Pharmacology and Cancer Biology. Dr. Tian's project will determine endoglin's roles in regulating signaling and biology in vascular smooth muscled cells (VSMCs) during developmental angiogenesis, as well as in the pathophysiology of HHT. Dr. Tian's research study will (1) determine how endoglin regulates signaling and biology in VSMCs; (2) determine endoglin's roles in VSMCs recruitment during vascular development; (3) define the mechanism by which endoglin regulates VSMC biology and recruitment; and (4) define the contribution of endoglin mutation in VSMCs to HHT disease. Collectively, these studies will provide novel insights into how endoglin in vascular muscle cells regulates physiological development and how its disruption in vascular smooth muscle cells contributes to HHT. These mechanistic insights will enable novel therapies targeting endoglin function to treat HHT patients.
Role of Endoglin in HHT and High Output Heart Failure
Simon Tual-Chalot, PhD, is a Post Doctoral Associate at Newcastle University working under the direction of Dr. Helen Arthur, Professor of Cardiovascular Biology. Endoglin is a protein that is found on the surface of the cells that line the blood vessels. When this protein is missing from these lining cells, known as enothelial cells, the heart enlarges rapidly to form a more muscular and bigger heart which puts undue strain on the heart and can lead to high output cardiac failure which is associated with HHT. The evidence so far suggests that endoglin is required in the blood vessels to regulate vascular resistance which is important for normal heart function. Dr. Tual-Chalot's project will use a mouse model which permits depletion of endoglin in endothelial cells to investigate how endoglin maintains the adult vasculature to protect against high output heart failure (HOHF). Dr. Tual-Chalot will (1) establish the timing and extent of the HOHF phenotype following endoglin depletion; (2) determine the role of endoglin in vasoregulations of resistance arteries; and (3) examine changes in vessel architecture following loss of endoglin. This knowledge will help to develop treatments for HHT patients with this heart condition.
Identification of Genetic Modifiers in HHT
Whitney Wooderchak-Donahue, PhD, is an Adjunct Assistant Professor, Department of Pathology at the University of Utah and a Research Investigator at ARUP Laboratories working under the direction of Dr. Pinar Bayrak-Toydemir. Mutations in ENG, ACVRL1, and SMAD4 cause HHT. However, this genetic heterogeneity does not explain the extremely variable clinical symptoms routinely seen with HHT families suggesting that genetic modifiers influence phenotypic variation. Dr. Wooderchak-Donahue's project is focused on identifying additional genetic modifiers in HHT. Dr. Wooderchak-Donahue hypothesizes that the variability of HHT is caused by mutations in additional genes or genetic modifiers critical to vascular development. She will test her hypothesis by (1) identifying genetic modifiers of the HHT phenotype in members of the same family who have an ENG or ACVRL1 mutation and (2) elucidate the genetic basis of vascular malformations in HHT families and patients who do not have a known ENG, ACVRL1 or SMAD4 mutation. These discoveries will help us understand the nature of genetic modifiers in HHT and will lead to better diagnostics for HHT patients with the addition of new genes to the HHT NGS panel, better genetic counseling and may ultimately lead to the development of new therapeutics for HHT.
An Innovative Gene Therapy by Selective and Regulative Neutralizing VEGF in HHT-Associated Brain Arteriovenous Malformations
Wan Zhu, PhD, is a Post Doctoral Research Fellow at the University of California, San Francisco working under the direction of Dr. Hua Su. Brain AVMs (bAVMs) have the most devastating outcomes due to the possibility of vessel rupture in the brain. Most current therapies are invasive and have high risks, therefore, there is a need for new treatment strategies. Previous studies have shown that an increased level of an angiogenic factor, vascular endothelial growth factor (VEGF), plays an important role in AVM formation. Inhibition of VEGF by an antibody drug such as bevacizumab (Avastin) reduces lesion sizes. However,antibody-treatment is very costly and has significant side effects. Dr. Zhu's project proposes an innovative and noninvasive strategy injecting a viral vector into the localized site to bind VEGF and inhibit VEGF pathogenic effects in AVMs. It is believed that this strategy can be used to treat bAVMs in HHT patients and with minor modifications this strategy can be used to treat HHT patients who have AVMs in other organs.
Cure HHT funded five of these research grants; the sixth grant was made possible by a very generous donor.
Robert I. White (RIW) Young HHT Clinician of the Year Award
The RIW Award was established in 2004 in recognition of Dr. Robert I. White Jr.'s outstanding contribution to HHT care and to mentoring other clinicians to develop expertise in HHT care and research. This award will be given annually to a clinician (physician or health professional) who is with the first years of work involving HHT and who embodies Dr. White's qualities as a compassionate and dedicated clinician, devoted to improving HHT care.
Nominations for the award will be requested annually by the Chair of the Global Research and Medical Advisory Board (GRMAB) and reviewed by a subcommittee of the GRMAB. The award will be presented at either the International Scientific HHT Conference or the National Patient and Family Conference.
Award: $2,500 (U.S.) and free registration to the next International Scientific HHT Conference will be awarded by the HHT Foundation International, Inc.
Dr.Tom Letteboer 2004 (The Netherlands)
Dr. Gaetan Lesca 2005 (France)