Sunday, April 28, 2024
4/28/2024
Blood flows through a well-organized network of vessels (arteries, veins, and capillaries) to allow proper nutrient and oxygen exchange throughout the body. In Hereditary Hemorrhagic Telangiectasia (HHT), blood vessel organization becomes disrupted, resulting in the formation of localized, enlarged direct connections between arteries and veins (arteriovenous malformations, AVMs) that bypass the normal capillary bed in major organs or entangled vessels (telangiectasias) at the skin and mucosa. These malformations can rupture and bleed into the surrounding area, and people with HHT often experience nosebleeds, anemia, stroke, and even death. HHT occurs in individuals with pathogenic variants of three major components of Transforming growth factor beta (TGF-ß) signaling - Smad-related protein 4 (SMAD4, JP-HHT), Endoglin (ENG, HHT1), or Activin receptor-like kinase-1 (ALK1, HHT2). While these germline-inactivating mutations are systemic, AVM formation is localized to major organs such as the brain, lungs, and liver. This leads us to wonder whether focal second hits, such as random somatic mutations or wounds, could lead to complete loss of function (loss of heterozygosity, LOH) and initiate AVM formation in a certain area. It was recently shown that some telangiectasias in HHT patients consist of cells with both mono-allelic and bi-allelic loss, which supports this idea of LOH. This project aims to develop an HHT mouse model of Smad4 LOH, compare it to previous Smad4 homozygous inducible knockout models, and explore the role of LOH in AVM formation in HHT. My central hypothesis is that i) the LOH model will offer a better alternative for studying the impact of second hits on HHT pathology and ii) localized, mosaic loss of function mutations lead to LOH-ECs influencing surrounding non-LOH ECs to initiate AVM formation. I will test this through two major aims that: 1) fully compare the Smad4 LOH model to the previous model and 2) evaluate the influence of Smad4 LOH on nearby cells and overall AVM formation. Exploring the role of LOH is a novel approach in HHT, as previous studies have focused solely on heterozygous or complete knockout but were lacking uniform heterozygosity coupled with localized complete loss of function. This project offers the potential to better represent HHT patients and further explore the pathobiology of this rare disease. Through this project, I will grow into a more independent scientist by developing my research communication, collaboration, and problem-solving skills. I will learn how to effectively design experiments, trouble shoot, and incorporate new, cutting-edge techniques such as spatial transcriptomics. From this training, I will develop the skills necessary to fulfill my immediate goal of working as a post doctorate in a neurovascular lab and long-term goal of obtaining a tenure-track position at an academic research institute.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
