We are both a basic and translational science laboratory. This means our lab studies genes, gene products, and cells on a molecular level and then studies how our molecular findings cause human disease. To involve patient samples in research, we recruit study subjects from among our clinical patients with vascular disease. Patient samples are crucial to learning more about conditions.

Our lab and other clinicians are curious—why do HHT patients only have arteriovenous malformations (AVM's) in some organs, like the lungs and liver, but not in other organs, like the heart? And why do some patients with HHT end up having lung AVMs while others do not?

We aim to learn more about HHT, the signaling pathways within endothelial cells (cells that line arteries and veins) that are affected by HHT, and how derangements in these pathways influence symptoms or organs affected.

Some specific long-term goals include:

• Identifying modifier genes or modifier mutations in other genes (NOT the genes causing HHT itself—ENG, ACVRL1, and SMAD4)
• Better understanding the BMP9 signaling pathway

These discoveries could lead to screening options and identification of targets for therapies (medications).

Identifying modifier genes or mutations may help clinicians better predict which HHT patients are more likely to develop lung AVM's, and therefore provide tailored medical care and screening. Modifier genes may also serve as therapeutic targets for medication development. Better understanding on the BMP9 signaling pathway may also provide therapeutic targets for drug development.

Currently, we are interested in samples from people with HHT, as well as their unaffected relatives. Samples from unaffected family members would be used as "controls" in our studies.

This is so we can sequence our candidate modifier gene, and identify any mutations or "single nucleotide polymorphisms" (SNPs) that could potentially be linked with prevalence and severity of lung AVMs.

Skin biopsies allow us to grow fibroblast cell lines in the lab, and further study gene and protein expression, signaling pathways, and otherwise better understand other molecular factors on cell function in HHT.

Skin biopsies from "affected" skin (telangiectasias) is helpful for looking at tissue-specific changes.

As discussed earlier, researchers and clinicians are curious why some organs are affected and others are not, or why only some people with HHT end up with lung AVM's, for example.

We think there may be tissue-specific changes, a sort of "second hits," that impact why some people with HHT have AVM's in lungs (or other organs). Having tissue samples directly from affected areas or organs will help us answer these questions. There may be changes in signaling, expression or otherwise in those cells, versus cells from cheek or blood.

That's great! We're happy to see another curious mind. Feel free to address any additional questions to our research genetic counselor, Annika Gillam, at aegillam@ucdavis.edu.