Genetics Research Laboratories
Genetics research in the Department of Neurosurgery is dedicated to improving the understanding and treatment of neurological disease, with a focus on intracranial aneurysms, brain tumors, and traumatic brain and spinal cord injury. Investigative approaches include genetic studies, basic biochemical analyses, developing animal models, and testing treatments in clinical trials.
GENETIC STUDIES ON INTRCRANIAL ANEURYSMS
One of the longterm goals of the Department of Neurosurgery is to determine the genetic basis of intracranial aneurysms, abnormal dilations or ‘bulges’ of intracranial blood vessels. Intracranial aneurysm rupture is the most common cause of spontaneous subarachnoid hemorrhage, which often leads to severe disability or death. Ten to twenty percent of intracranial aneurysm patients have a positive family history for aneurysms or aneurysmal rupture and there is up to a five-fold increased risk of aneurysm incidence among first-degree relatives compared to the general population. The identification of genetic determinants may provide not only a deeper understanding of aneurysm pathobiology, but also facilitate the development of diagnostic tools for identifying individuals at increased risk for aneurysm formation or rupture. In addition, novel targets for therapeutic intervention may be identified. Three research programs in the Department are contributing to this effort led by Drs. John Hagan, Yanning Rui, and Zhen Xu with support from the Department of Neurosurgery Neuroscience Research Repository led by Dr. Georgene Hergenroeder.
Dr. Hagan’s intracranial aneurysm research is focused on using clinical human genetics and animal models to discover novel gene mutations that contribute to intracranial aneurysm development and to define dysregulated pathways in disease that are potential therapeutic targets. Of note, recent research with multiple collaborators has identified THSD1 as a bona fide IA-causing gene whose mutation causes intracranial aneurysms in both familial and sporadic cases with supporting evidence from both zebrafish and genetically engineered mouse models. Recently, we analyzed additional large families with at least four individuals affected by disease, identifying additional candidate genes using whole exome sequencing. Future studies are planned to use whole genome sequencing in both families and our large patient cohort to analyze the genome comprehensively to identify which candidate genes are associated with disease.
SIGNALING IN INTRCRANIAL ANEURYSM
Dr. Yanning Rui’s research group is dedicated to elucidating the pathogenic and cellular mechanisms that contribute to intracranial aneurysm (IA) disease. In the past few years, we established a novel genetic model of IA by inactivating THSD1 in mice. Using this model, Dr. Rui’s lab identified the association between dysregulated autophagic activity and IA development. As a self-digestion system, autophagy degrades cellular components under different stresses that can be triggered by pathological changes. Autophagy is upregulated during IA pathogenesis and in turn degrades focal adhesions (FAs). In vascular system, FAs can adhere endothelial cells to its extracellular matrix. FAs are critical for vascular stability as the loss of FAs disrupts the cell-matrix interaction, induces hemorrhage and frequently occurs in IA lesions. Studies from Dr. Rui’s lab suggested that IA-related, autophagy-mediated FA turnover is selective. Recently, we defined “FA-phagy” for the process in analogy to other types of selective autophagy like ER-phagy or NPC-phagy. Targeting FA-phagy may improve vascular integrity and prevent IA growth and rupture.
Although genetic models provide invaluable insights into IA pathogenesis, we are constantly curious about whether these new mechanisms are also exploited in other experimental models. Most IA cases are sporadic and thus it is important to validate them in experimental models that more closely mimic the pathophysiology of IA in non-familial cases. One research focus of Dr. Zhen Xu is to develop new experimental IA models. In his lab, a variety of IA risk factors such as abnormal wall shear stress, hypertension, smoking and aging are strategically introduced to the mouse model, where a high incidence of IA was observed. Biochemical analyses on the early events during IA development revealed the formation of “podosomes” in endothelial cells. These podosomes degrade basement membrane, a thin sheet-like extracellular matrix underneath the endothelium. Degradation of extracellular matrix compromises cerebrovascular integrity and contributes to IA development. Podosome formation and function can be regulated by different signaling pathways such as SRC, TGF-beta and Notch, which may serve as promising therapeutic targets for IA.
MICRORNAS IN BRAIN CANCER
We are also interested in identifying novel genetic risk factors associated with cancer, including those that occur in the brain. Specifically, a newly discovered class of RNA regulatory molecules called microRNAs have been shown to be critical in some cases for tumor formation and progression. Three laboratories are spearheading these efforts led by Drs. John Hagan, Hui-Wen Lo, and Tae Jin Lee.
The laboratory of Dr. John Hagan is actively pursuing understanding the role of microRNAs and their regulators in cancer with an aim of developing next generation therapeutics. Dr. John Hagan leads a project to understanding the role of microRNA in meningiomas, which account for 20% of all central nervous system tumors. Previously, Dr. John Hagan in collaboration with researchers at The Hospital for Sick Children in Toronto have defined microRNA expression signatures in medulloblastoma, the most common pediatric brain cancer, that classify medulloblastoma subtypes and stratify disease outcomes. In addition, Dr. Hagan has discovered that the proto-oncogene LIN28 represses the tumor suppressor let-7 microRNAs in multiple cancer types. LIN28 overexpression and let-7 repression is associated with poor prognosis in a myriad of cancer types, including glioblastoma multiforme, medulloblastoma, neuroblastoma, atypical teratoid/rhabdoid tumors, multiple myeloma, liver, breast, ovarian, and colon cancers. LIN28 via a let-7 dependent mechanism is believed to promote poor cancer prognosis by promoting resistance to several frontline cancer treatments including ionizing radiation and multiple chemotherapy drugs. Efforts are ongoing to target the LIN28/let-7 pathway to improve patient outcomes.
Dr. Hui-Wen Lo’s lab has a long-standing interest in studying the role of microRNAs in primary and metastatic brain tumors. Her lab has recently reported that brain-metastatic breast cancer secretes extracellular vesicle-derived miR-1290 to activate astrocytes in the brain metastatic niche through the miR-1290-FOXA2-CNTF signaling axis. Consequently, miR-1290-activated astrocytes secrete CNTF cytokine to promote the growth of breast cancer brain metastases. Lo Lab has ongoing projects in the lab to investigate additional micoRNAs for their roles in promoting breast cancer brain metastases and glioblastoma progression.
Lee laboratory focuses on basic and translational studies on a role of deregulated microRNAs in tumorigenesis and developing a strategy to treat brain tumors using cutting edge RNA-based nanoparticles. Brain tumors are the second-leading cause of cancer-related death with limited options of treatment. Dr. Lee’s research mainly involves novel nanoparticle based on pRNA derived from the DNA packaging motor of bacteriophage Phi29 for successful delivery of therapeutic microRNAs into brain tumors. They developed a new RNA nanoparticle loaded with various siRNA or microRNA by engineering pRNA from phi29, and further modified them to fit for tumor cell recognition, internalization and delivery of cargo RNA molecule. First batch of RNA nanoparticle has shown to successfully penetrate the blood brain barrier and deliver a cargo siRNA of Luciferase reporter gene in mice model system bearing intracranial tumor, provided a proof-of-concept for efficient delivery of therapeutic RNAs for the treatment of brain tumors. When the anti-miR-21 carrying RNA nanoparticles were systemically administered, growth of glioblastoma xenograft in mouse brain was significantly reduced through reactivation of multiple tumor suppressors released from suppression by the elevated miR-21.
STEM CELL THERAPY RESEARCH
Dr. Jiaqian Wu oversees the efforts of the stem cell group, working to translate basic discoveries into a treatment for spinal cord injury. This work was initially in collaboration with Mr. Staman Ogilvie and supported by the Ogilvie Fund for Spinal Cord Injury, Recovery, Rehabilitation & Research. The goal of this project is to design new therapies to improve motor function of those paralyzed by spinal cord injury by the end of the decade. Each scientist in the group was specifically recruited to work together with complementary skill sets to develop therapeutic stem cells that can be tested in clinical trials. For more information, please visit the Stem Cells Research page.
TRAUMATIC BRAIN INJURY AND SPINAL CORD INJURY
The National Center for Testing Treatments for Chronic Spinal Cord and Traumatic Brain Injury (NCTT) is a research network that aims to develop treatments to improve the neurological and motor functions of persons living with spinal cord injuries (SCI) and traumatic brain injuries (TBI) and to reduce the premature mortality rates associated with these conditions.
The Center’s approach toward developing treatments involves multiple concurrent initiatives. The NCTT obtains detailed medical histories, performs examinations and functional tests, and reviews available imaging studies from eligible patients. Potential subjects’ blood samples are also banked and analyzed so that DNA is available to evaluate how patients’ responses to injury as well as treatment are related to their genetic background. Every patient is specifically and thoroughly classified by type and severity of injury, medical issues (e.g., depression, neuropathic pain, recurrent infections, skin breakdown), and current level of neurological function. In combination, the aforementioned steps enable the NCTT to classify subjects’ research interests and injury characteristics in order to offer them appropriate, desirable research opportunities.