Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease (~1/5, 000), caused predominantly by mutations in ENG or ACVRL1 aka ALK1 encoding TGF?/BMP receptors. Patients develop vascular malformations, including small mucocutaneous telangiectases and/or large visceral arteriovenous malformations (AVMs) in multiple organs. The penetrance and expressivity of clinical manifestations is highly variable between patients, even within a family. The rationale for the project is that investigation of the biological and molecular characteristics of cells circulating within blood, especially circulating endothelial progenitor cells (CEPCs), will provide important new knowledge about basic cellular and molecular mechanisms of HHT pathobiology, and contribute to development of prognostic HHT markers. The over- arching hypotheses to be tested are: a) the cellular makeup of circulating bone marrow-derived cell populations is perturbed in the blood of HHT patients;b) there is an elevation of CEPC numbers in HHT that contributes to and correlates with disease pathology including telangiectases and AVMs;c) gene expression networks are perturbed within HHT CEPCs to alter their biological functions, and d) HHT genetic modifiers regulate CEPC numbers and biology. The extent to which cellular and molecular perturbations correlate with disease type (HHT1 versus HHT2) and disease severity will be tested, and molecular mechanisms investigated using cultured EC from HHT bloods.
Aim 1) multi-color FACS analysis will be utilized to assess perturbation in circulating cell numbers in HHT patients and HHT mouse models, focusing on CEPCs and monocytes.
Aim 2) CEPCs will be isolated from blood of HHT patients and controls, and utilized to investigate alterations in clinically-relevant parameters of in vitro angiogenesis, and biological effects of siRNA knock down of HHT modifier genes. A bank of CEPC-derived iPS cells will be generated for use by the HHT community.
Aim 3) Blood cell mRNA and miRNA transcriptomic profiles will be compared between wild type, Eng+/- and Alk1+/- mice. Blood gene expression networks will be generated from existing transcriptomic data available from genetically heterogeneous mouse (>100) and human (>100) populations. Finally, new transcriptomic data will be generated from human HHT1, HHT2 and control blood, to test the postulate that gene expression networks are rewired within HHT CEPCs and/or monocytes to alter cellular parameters that can be molecularly probed in Aim 2 in order to provide mechanistic insight into HHT disease mechanisms.

Public Health Relevance

This project will investigate whether cells isolated from Hereditary Hemorrhagic Telangiectasia (HHT) patient blood can be used to probe the detailed cellular and molecular mechanisms of this vascular disease. The approach would provide a non-invasive platform for disease studies in human tissue, and may provide informative that can be used to develop biomarkers of disease severity in HHT.

National Institute of Health (NIH)
High Priority, Short Term Project Award (R56)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Mcdonald, Cheryl
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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