An intracranial aneurysm (IA) is a focal dilatation of an arterial blood vessel in the brain. The rupture of IA causes subarachnoid hemorrhage (SAH), the most fatal form of stroke. Due to SAH, around 30% will die before reaching hospital, 40% of survivors die within a week, and more than half will never return to independent living. In the United States, annually, 30,000 people will suffer a ruptured IA. Unfortunately, IA is often asymptomatic and there are no drugs to treat IA. Lack of knowledge about the genetic factors that contribute to disease greatly impedes our understanding of pathogenesis and attempts to find new therapeutic avenues. Recently, our group identified the first IA-causing gene thrombospondin type 1 domain containing 1 (THSD1), in which multiple loss-of-function rare variants were found in a subset of IA/SAH patients. Animal studies showed that THSD1 is required for cerebrovascular integrity since intracranial hemorrhage was observed in Thsd1-deficient zebrafish and mice. Our data suggest that focal adhesion loss is responsible for the above phenotypes. However, the cellular and molecular mechanisms by which THSD1 variants compromise focal adhesion stability and cerebrovascular integrity remain unknown. Based on our preliminary data, we hypothesize that autophagy, a self-eating system, is the missing link between THSD1 and focal adhesion stability and cerebrovascular integrity. As numerous compounds targeting autophagy have been developed, our study provides a novel therapeutic target that can be manipulated pharmacologically. Importantly, the role of autophagy in IA formation has never been studied and our proposal raises a novel concept that autophagy plays a pathogenic role in IA formation. In particular, we will define how THSD1 regulates autophagy in vivo and establish the role of autophagy in THSD1-mediated focal adhesion stability. Moreover, we will determine how autophagy contributes to THSD1-mediated cerebrovascular integrity in two vertebrate models, zebrafish and mouse. A panel of autophagy inhibitors including three FDA-approved drugs (e.g., verteporfin, clomipramine, and chloroquine) will be evaluated in terms of preventing or treating cerebral hemorrhage in zebrafish and IA formation in mice. To provide insight into THSD1-mediated IA pathogenesis, we will evaluate the effect of THSD1 variants on autophagy, focal adhesion stability, and cerebrovascular integrity in comparison with wide-type THSD1.
THSD1 has been identified as the first causal gene for both familiar and sporadic cases in a subset of intracranial aneurysm patients, who tend to suffer from aneurysmal subarachnoid hemorrhage, the most fatal form of stroke. The goal of this research is to characterize the downstream of THSD1 signaling pathway, in which a self-eating cellular mechanism called autophagy contributes to THSD1-mediated intracranial aneurysm pathogenesis. Since numerous compounds targeting autophagy including three FDA-approved drugs have been developed, our project provides a novel and convenient therapeutic target for intracranial aneurysm patients.
