# Role of THSD1 and its Disease Causing Variants in Intracranial Aneurysm

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $336,875

## Abstract

An intracranial aneurysm (IA) is a weakened area in a cerebral artery wall that leads to
abnormal dilation and may rupture causing subarachnoid hemorrhage (SAH). Despite treatment
advances, the mortality of aneurysmal rupture is over 40%, and only one-half of survivors return
to independent life. In the United States alone, approximately 30,000 SAH cases occur
annually. Prior to rupture, IAs are usually asymptomatic and typically go unnoticed. When
identified and treated before rupture, survival rates dramatically improve. Therefore, early
detection, proper monitoring, and timely treatment of IAs are of paramount importance in
preventing disability and premature death. Our research team recently implicated rare variants
in thrombospondin-type 1 domain-containing protein 1 (THSD1) in both familial and sporadic IA
and SAH cases using human genetics and animal models. THSD1 is a poorly characterized
gene whose expression is largely restricted to endothelial cells. Here, we seek to elucidate the
key roles of THSD1 in brain vascular endothelial cells, using both a mouse knockout and human
brain endothelial cells. We will test the hypothesis that harmful THSD1 variants impair
endothelial cell function by perturbing focal adhesions leading to dysregulated signaling
mediated through focal adhesion kinase (FAK). This hypothesis is supported by our preliminary
data that includes an unbiased global pathway analysis of THSD1 human brain microvascular
endothelial knockdown cells. We anticipate that this research will elucidate in part the underlying
mechanism that leads to IA formation and rupture. Additionally, new discoveries will be made
with potential clinical impact for the early diagnosis and treatment of intracranial aneurysms,
thereby reducing morbidity and mortality. This work also has broader implications in vascular
biology as emerging evidence implicates Thsd1 in endothelial barrier function and in protection
of the vasculature in atherosclerotic and hemorrhagic lesions.

## Key facts

- **NIH application ID:** 10133749
- **Project number:** 5R01NS104280-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Dong H Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133749

## Citation

> US National Institutes of Health, RePORTER application 10133749, Role of THSD1 and its Disease Causing Variants in Intracranial Aneurysm (5R01NS104280-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133749. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*