Genetics Laboratory of Dong H. Kim, M.D.
The laboratory of Dong H. Kim, M.D., is dedicated to improving the understanding and treatment of neurological disease, with a focus on cerebral 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.
One goal of our lab 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 pursuit of this goal, our lab has had several noteworthy successes. We recently discovered how a specific mutation in the THSD1 gene contributes to the pathophysiology of intracranial aneurysms. By examining a well-characterized and clearly defined cohort of patients and families affected by this type of aneurysm, we have identified the first genetic cause in a single large family, then extended this finding to other unrelated patients and families. To do so, we enrolled more than 100 affected families and clinically characterized more than 500 IA (intracranial aneurysm) probands. By performing whole exome sequencing on a large family, we were able to reveal a segregating nonsense THSD1 mutation.
Additional THSD1 mutations were then noted in 8 unrelated probands, both familial and sporadic. Thsd1 loss-of-function studies in zebrafish and mice were then used for in vivo analyses, and functional studies were performed using an in vitro endothelial cell model. We discovered Thsd1 loss-of-function in zebrafish and mice caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in intracranial aneurysm patients. These findings have provided new insight into intracranial aneurysm pathogenesis and new understanding of the overall function of THSD1, a protein that has been poorly characterized to date.We are also interested in identifying novel genetic risk factors associated with brain tumors. One of our projects involves understanding the role of microRNA in meningiomas, which account for 20% of all central nervous system tumors.
Although studies have elucidated several key genes in the development and progression of these tumors, none have been utilized in a grading system or to predict clinical outcomes. Our research examines miRNAs that have been found to be differentially expressed in meningiomas in order to determine their involvement in tumor development and progression. Determining what we believe to be the significant role of miRNAs in the regulation of gene expression is crucial to better understanding meningioma pathogenesis, and could potentially elucidate a molecular mechanism for predicting their clinical behavior independent of their histology.
Another project concerns familial meningiomatosis, a clinical diagnosis given to individuals with a personal history of multiple meningiomas and/or families with multiple relatives affected by meningioma with otherwise no other disease-inducing environmental exposure. Candidate genes have been proposed that may account for a proportion of reported cases, but additional disease-associated genes are yet to be identified. In an effort bridge this gap in knowledge, we are currently collecting cohorts of patients who meet the criteria for a familial meningiomatosis clinical diagnosis as well as others who have a personal history of multiple brain tumors, multifocal disease, or a positive family history of brain tumors for whole exome sequence analysis.
Furthermore, we are in the process of identifying genetic variants that modify our patients’ reactions to therapy or injury. As with drug reactions, there are wide differences in reactions to trauma (like swelling or the likelihood of hydrocephalus), or pain. We are currently collecting cohorts of these patient outliers for whole exome sequencing analysis with the hope that by recognizing those genetic differences between the opposing groups, we will begin to distinguish causal genetic factors that account for severe reactions to therapeutic interventions.
STEM CELL THERAPY
Dr. Kim oversees the efforts of the stem cell group, four scientists working to translate basic discoveries into a treatment for spinal cord injury. This work is 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
Developed by Dr. Kim with Georgene Hergenroeder, R.N., M.H.A, and Pramod Dash, Ph.D., The National Center for Testing Treatments for Chronic Spinal Cord and Traumatic Brain Injury (NCTT) is a multicenter 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). As a national network, the NCTT will collaborate with established patient support and advocacy groups as well as other medical institutions.
The Center’s approach involves the identification and enrollment of patients only in the chronic, stable phase of injury. The testing of treatments will also occur in the chronic phase, a different approach from most clinical trials, which usually occur in the acute period. The advantages of this approach include the ability to carefully characterize patients before intervention, allowing the patient to serve as his or her own control. It also allows the patients to be identified before a therapeutic trial, and creates a large database of potential subjects.
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. These steps enable the NCTT to classify subjects’ research interests and injury characteristics in order to offer them appropriate, desirable research opportunities.
Among the upcoming NCTT research programs is a project that aims to investigate the positive impact of Transcranial Magnetic Stimulation on persons with TBI and SCI (in collaboration with Brent Masel, M.D. of the Transitional Learning Center). Evidence suggests that repetitive Transcranial Magnetic Stimulation (rTMS) in combination with physical therapy may be a promising treatment to improve motor function and reduce central neuropathic pain.
Another example is the Nerve Transfer Study that analyzes the degree to which transfer of shoulder movement nerves to intact hand movement nerves may restore partial hand function in certain patients with cervical SCI. This study, in collaboration with Zach Ray, M.D. at Washington University, is currently undergoing IRB review.
INNOVATION AND QUALITY UNIT
Dr. Kim directs the Innovation and Quality (IQ) Unit, a team of statisticians, database managers, programmers, nurses, and coordinators that support Departmental quality improvement initiatives and research efforts by the faculty. This team creates databases, obtains accurate and valid clinical data, performs analyses, generates reliable reports, and maintains regulatory compliance. The IQ unit communicates regularly with the hospital coding team, the revenue cycle team, and other staff in order to help us understand the rules of coding and the strict guidelines set by the federal government. They also monitor mortality and complication rates.
In addition to work done on performance monitoring and improvement, the IQ unis assists research in two ways. First, the IQ unit maintains the Neuroscience Research Repository (or NRR), under the direction of Georgene Hergenroeder. The NRR is a prospective database and sample bank created to collect patient information and samples for current and future neuroscience research.
The NRR team enrolls all admitted patients prospectively. Consents allows the NRR to gather clinically recorded admission data and longitudinal data for up to an additional 15 years after discharge. In addition, discarded samples such as blood, cerebrospinal fluid and tissue (e.g. tumors) can be taken and stored. Family members of select groups of patients will also be approached for enrollment. This is a large biobank that couples bio-samples with clinical data. In addition, our approach is to treat each patient as a research subject, and collect data as part of routine patient care.
Samples and data are labeled with a study code to maintain confidentiality. Samples and data are maintained in secure, limited-access environments with back-up/redundancy procedures in place. Faculty investigators can request samples which are distributed after approval from the Neurosurgery Scientific Review Committee and the Committee for the Protection of Human Subjects (CPHS). These samples are specifically prepared and maintain for genomic and proteomic analyses.
A second IQ team research function is to assist in conducting clinical trials. Research assistants are in the hospital 24/7, not only to enroll patients into the NRR and gather samples, but also to help identify, enroll, and randomize patients into acute clinical trials. For example, the IQ team supports the “HOPES” trial, a multicenter, randomized clinical trial investigating the effect of HypOthermia for Patients requiring Evacuation of Subdural Hematoma (PI: Dong Kim). HOPES is a prospective, controlled, multi-center trial that aims to test whether treating TBI patients with hypothermia prior to surgical evacuation of a subdural hematoma improves their long-term prognosis. HOPES has over 22 participating sites in the United States and Japan, and will test the hypothesis that hypothermia reduces the reperfusion injury that can occur with hematoma evacuation, improving outcomes.
Dong H. Kim, M.D., Principal Investigator
John H. Hagan, Ph.D., Co-Investigator
Pramod Dash, Ph.D., Co-Investigator
Yanning Rui, Ph.D., Postdoctoral Research Fellow
Zhun Xu, Ph.D., Postdoctoral Research Fellow
Krista Qualmann, M.S., C.G.C., Genetic Counselor
Lisa Schmitt, R.N., Nurse Manager
Jacob Cammarata, R.N., Research Nurse
Amish Amin, R.N., Research Nurse
Rita Cole, DPT, Physical Therapist
Airu Niu, Ph.D., Research Assistant
Georgene Hergenroeder, M.H.A., R.N., Co-Investigator
Joanna O’Leary, Ph.D.
Rahil Tai, M.D.
Karina Wlostowska, BA
Lisa Schmitt, R.N., Nurse Manager
Marcia Kerr, R.N., Pediatric Studies
Greg Lu, M.D.
Nasim Rezanejad, M.D.
Daniel Saenz, M.S.
1. Santiago-Sim T, Fang X, Hennessy M, Nalbach S, DePalma S, Lee MS, Greenway S, McDonough B, Hergenroeder G, Patek K, Colosimo S, Qualmann K, Hagan JP, Milewicz D, MacRae C, Dymecki S, Seidman C, Seidman JG. Kim DH. Mutations in THSD1 as a Cause of Intracranial Aneurysm. (forthcoming). 2016.
2. Avidan N, Tran-Fadulu VT, Chen JH, Yu RK, Mathew S, Pannu H, Guo DC, Yuan J, Stankiewicz P, Yatsenko SA, Ahn C, Braverman AC, Willing MC, Abuelo D, Kim DH, Shete S, Milewicz DM. A Novel Locus for Familial Thoracic Aortic Aneurysms and Dissection Mapped to 15q24-26 (TAAD3): Locus Specific Phenotypes for Familial Aortic Disease. Circulation. In press.
3. Li, S, Xue, H, Wu JB, Rao, MS, Kim, DH, Deng, W, and Liu, Y. Human iPSC NEUROG2 dual knockin reporter lines generated by the CRISPR/Cas9 system. Stem Cells Dev. Ahead of print Sept 28, 2015.
4. Lin Y, Chen Y, Wang Y, Yang J, Zhu V, Cui X, W Yan, Jiang T, Fletcher S, Levine J, Kim DH, Tandon N, Zhu J, Li M. ZIP4 is a Novel Molecular Marker for Glioma. Neuro-Oncology. 2013;15:1008-16.
5. Li J, Bian K, Kim DH, Ashley WW, Nath R, McCutcheon I, Fang B, Murad F. Targeting different types of human meningioma and glioma cells using a novel adenoviral vector expressing GFP-TRAIL fusion protein from hTERT promoter. Cancer Cell International. 2011;11:35
6. Milewicz DM, Østergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, Bradley TJ, Olney AH, Adès L, Maher JF, Guo D, Buja LM, Kim DH, Hyland JC, Regalado ES. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J. Hum Genet. 2010;152A:2437–2443.
7. Tran-Fadulu V, Pannu H, Kim DH, Vick GW 3rd, Lonsford CM, Lafont AL, Boccaladro C, Smart S, Peterson KL, Hain JZ, Willing MC, Coselli JS, LeMaire SA, Ahn C, Byers PH, Milewicz DM. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet. 2009;46:607-13.
8. Krishna V, Kim DH. Ethnic Differences in Risk Factors for Subarachnoid Hemorrhage. J Neurosurg. 2007;107:522-9.
9. Guo DC, Pannu H, Tran-Fadulu VT, Papke C, Yu RK, Avidan N, Divecha D, Scherer S, Estrera A, Safi H, Vick III GW, McConnell V, Marian AJ, Kim DH, Tung PP, Buja LM, Rama CS, Shete S, Milewicz DM. Mutations in genes encoding smooth muscle contractile proteins, ACTA2 and MYH11, cause hyperplastic vasculomyopathy and lead to diffuse and diverse vascular diseases. Nature Genetics. 2007;39:1488-93.
10. Santiago-Sim T, Depalma SR, Ju KL, McDonough B, Seidman CE, Seidman JG, Kim DH. Genomewide linkage in a large Caucasian family maps a new locus for intracranial aneurysms to chromosome 13q. Stroke. 2009;40:S57-S60.
11. Pannu H*, Kim DH*, King T, Guo D, Shete S, Van Ginhoven G, Chin T, Chang K, Oi Y, Milewicz DM (*Authors’ contributions equal). Association of MMP2 and MMP9 polymorphisms with intracranial aneurysms. J Neurosurg. 2006;105:418-23.
12. Kim DH, Van Ginhoven G, Milewicz DM. Familial aggregation of both aortic and cerebral aneurysms: evidence for a common genetic basis in a subset of families. J Neurosurg. 2005;56:655-61.
13. Pannu H, Kim DH, Seaman R, Van Ginhoven G, King T, Vollmer DG, Shete SS, Milewicz DM. The ACE insertion/deletion polymorphism is not associated with intracranial aneurysms in a U.S.-derived Caucasian population. J Neurosurg. 2005;103:92-6.
14. Kim DH, Tu C, Cassacia-Bonnefil P, Chao M. The neurotrophins prevent apoptotic but not necrotic cell death following neuronal injury by signaling through the trk receptor. J Neurosurg. 2004;100:79-87.
15. Kim DH, Van Ginhoven G, Milewicz DM. The incidence of familial intracranial aneurysms in 200 patients: comparison between Caucasian, African-American, and Hispanic populations. Neurosurgery. 2003;53:303-8.
16. Mautes AEM, Kim DH, Sharp FR, Panter S, Sato M, Maida N, Bergeron M, Guenther K, Noble LJ. Induction of heme-oxygenase-1 (HO-1) in the contused spinal cord of the rat. Brain Research. 1998;795:17-24.
17. Mohapatra G, Moore DH, Kim DH, Grewal L, Hyun WC, Waldman F, Pinkel D, Feuerstein BG. Analyses of brain tumor cell lines confirm a simple model of relationships among fluorescence in situ hybridization, DNA index, and comparative genomic hybridization. Genes, Chrom, Cancer. 1997;20:311-9.
18. Kim DH, Gutin P, Noble LJ, Nathan D, Ross G, Yu JS, Nockels RN. Genetically engineered fibroblasts secreting nerve growth factor or brain-derived growth accelerates recovery from acute, traumatic spinal cord injury in the rat. Neuroreport. 1996;7.
19. Mohapatra G, Kim DH, Feuerstein BG. Detection of multiple gain and losses in ten glioma cell lines by comparative genomic hybridization. Genes, Chrom, Cancer. 1995;13:86-93.
20. Kim DH, Mohapatra G, Bollen A, Waldman FM, Feuerstein BG. Chromosomal abnormalities in glioblastoma multiforme and glioma cell lines detected by comparative genomic hybridization. Int J Cancer. 1995;60:812-815.