Dong H. Kim，医学博士的遗传学实验室
实验室Dong H. Kim，医学博士，致力于改善对神经系统疾病的理解和治疗，重点是脑动脉瘤，脑肿瘤，脑部外伤和脊髓损伤。研究方法包括遗传研究，基本的生化分析，开发动物模型以及在临床试验中的测试治疗。
遗传研究
我们实验室的目标之一是确定颅内动脉瘤，异常扩张或颅内血管的“凸起”的遗传基础。颅内动脉瘤破裂是自发性蛛网膜下腔出血的最常见原因，通常导致严重的残疾或死亡。十到20％的颅内动脉瘤患者的动脉瘤或动脉瘤破裂具有阳性的家族史，与普通人群相比，一级亲属的动脉瘤发生率的风险增加了五倍。遗传决定因素的识别不仅可以更深入地了解动脉瘤病原体学，而且还可以促进开发诊断工具，以识别识别出增加动脉瘤形成风险或破裂风险的个体的诊断工具。
为了实现这一目标，我们的实验室取得了一些值得注意的成功。最近，我们发现THSD1基因中的特定突变如何促进颅内动脉瘤的病理生理。通过检查由这种类型的动脉瘤影响的患者和家庭的特征良好，明确定义的患者和家庭，我们已经确定了一个大型家庭中的第一个遗传原因，然后将此发现扩展到其他无关的患者和家庭。为此，我们招募了100多个受影响的家庭，并在临床上表征了500多个IA（颅内动脉瘤）概率。通过对大型家庭进行整个外显子组测序，我们能够揭示出隔离的无意义THSD1突变。
然后在家族性和零星的8个无关的探针中发现了其他THSD1突变。然后将斑马鱼的功能丧失研究和小鼠进行体内分析，并使用体外内皮细胞模型进行功能研究。我们发现斑马鱼的功能丧失，小鼠引起了脑出血（将其定位于小鼠的亚蛛网膜下腔）并增加死亡率。从机械上讲，THSD1损耗损害了对基底膜的内皮细胞局灶性粘附。这些粘附缺陷可以通过在颅内动脉瘤患者中鉴定出的野生型THSD1的表达来挽救这些缺陷。这些发现为颅内动脉瘤发病机理和对THSD1的总体功能的新理解提供了新的见解，THSD1的整体功能是迄今为止特征的蛋白质，我们也有兴趣识别与脑肿瘤相关的新型遗传危险因素。我们的项目之一涉及了解microRNA在脑膜瘤中的作用，占中枢神经系统肿瘤的20％。
尽管研究已经阐明了这些肿瘤的发育和发展中的几个关键基因，但在分级系统中都没有使用或预测临床结果。我们的研beplay苹果手机能用吗究研究了在脑膜瘤中发现的miRNA，以确定它们参与肿瘤发育和进展。确定我们认为miRNA在基因表达调节中的重要作用对于更好地理解脑膜瘤的发病机理至关重要，并且有可能阐明一种分子机制来预测其临床行为与其组织学无关。
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.
干细胞疗法
金博士负责监督干细胞组的努力，四名科学家致力于将基本发现转化为脊髓损伤的治疗方法。这项工作与雄蕊Ogilvie先生合作，并得到了Ogilvie脊髓损伤，康复，康复和研究的支持。beplay苹果手机能用吗该项目的目的是设计新疗法，以在十年结束前改善因脊髓损伤而瘫痪的疗法。该小组中的每个科学家都被专门招募与互补的技能组合，以开发可以在临床试验中测试的治疗干细胞。有关更多信息，请访问干细胞研究beplay苹果手机能用吗page.
创伤性脑损伤和脊髓损伤
由Kim博士与Georgene Hergenroeder，R.N.，M.H.A和Pramod Dash博士开发，国家的慢性脊髓和创伤性脑损伤治疗中心（NCTT）是一个多中心研究网络，旨在开发治疗方法，以开发治疗方法beplay苹果手机能用吗改善患有脊髓损伤（SCI）和创伤性脑损伤（TBI）的人的神经系统和运动功能。作为国家网络，NCTT将与已建立的患者支持和倡导团体以及其他医疗机构合作。
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
金博士指导Innovation and Quality (IQ) Unit，由统计学家，数据库经理，程序员，护士和协调员组成的团队，这些团队支持该学院的部门质量改进计划和研究工作。beplay苹果手机能用吗该团队创建数据库，获得准确且有效的临床数据，执行分析，生成可靠的报告并维持法规合规性。智商部门定期与医院编码团队，收入周期团队和其他员工进行沟通，以帮助我们了解编码规则以及联邦政府制定的严格指南。他们还监测死亡率和并发症率。
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.
样本和数据标记为研究代码以保持机密性。样品和数据在安全的，有限的访问环境中维护，并进行了备份/冗余程序。教师调查人员可以要求在神经外科科学审查委员会和保护人类受试者委员会（CPHS）批准后分发样品。这些样品是针对基因组和蛋白质组学分析的特定制备并维护的。
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.
团队成员
Dong H. Kim，医学博士，首席研究员
约翰·H·哈根（John H. Hagan）博士，共同研究员
Pramod Dash, Ph.D., Co-Investigator
Yanning Rui博士，博士后研究员beplay苹果手机能用吗
Zhun Xu博士，博士后研究员beplay苹果手机能用吗
Krista Qualmann，M.S.，C.G.C。，遗传顾问
丽莎·施密特（R.N.），护士经理
Jacob Cammarata, R.N., Research Nurse
Amish Amin，R.N。，研究beplay苹果手机能用吗护士
丽塔·科尔（Rita Cole），DPT，物理治疗师
Airu Niu博士，研究助理beplay苹果手机能用吗
Georgene她genroeder, M.H.A., R.N., Co-Investigator
Miriam Morales
Alex Liu
乔安娜·奥利里（Joanna O’Leary）博士
Rahil Tai, M.D.
Karina Wlostowska, BA
丽莎·施密特（R.N.），护士经理
Marcia Kerr，R.N。，儿科研究
Mariel Arheler
阿曼达·布里斯科（Amanda Brisco）
Greg Lu, M.D.
Mayank Rao
Nasim Rezanejad，医学博士
Aditya Sanzgiri
Daniel Saenz，硕士
Glenda Torres
选定的出版物
1. Santiago-Sim T，Fang X，Hennessy M，Nalbach S，Depalma S，Lee MS，Greenway S，McDonough B，Hergenroeder G，Patek K，Patek K，Colosimo S，Valmmann K，Hagan JP，Milewicz D，Macrae C，Macrae C，Dymecki C，DymeckiiS，Seidman C，Seidman JG。金DH。THSD1的突变是颅内动脉瘤的原因。（即将到来）。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和Liu，Y。HumanIPSC Neurog2双重敲击蛋白记者线由CRISPR/CAS9系统产生。干细胞开发。2015年9月28日在印刷之前。
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，MuradF。使用新型的腺病毒载体靶向不同类型的人脑膜瘤和神经胶质瘤细胞，表达来自HTERT启动子的GFP-Trail融合蛋白。癌细胞国际。2011; 11：35
6. Milewicz DM，ØstergaardJR，Ala-Kokko LM，Khan N，Grange DK，Mendoza-Londono R，Bradley TJ，Olney AH，AdèsL，Maher JF，Guo D，Guo D，Buja LM，Kim LM，Kim DH，Kim DH，Kim DH，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Hyland JC，Regalado ES ES Regalado ES。DE NOVO ACTA2突变引起多系统平滑肌功能障碍的新综合征。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，Hain JZ，Willing MC，Coselli JS，Lemaire JS，Lemaire JS，Lemaire SA，Ahn C，Ahn C，Byers PH，Byers PH，PH，Byers ph，PH，Byers ph，Milewicz DM。通过TGFBR1或TGFBR2突变引起的胸动脉瘤和解剖的多代家族分析。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。大型高加索家族中的全基因组连接图将颅内动脉瘤的新基因座绘制为13q染色体。中风。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（*作者的贡献相等）。MMP2和MMP9多态性与颅内动脉瘤的关联。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.金正日DH,涂C, Cassacia-Bonnefil P,曹国伟mneurotrophins 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。通过比较基因组杂交检测到的多形和神经胶质瘤细胞系的染色体异常。国际癌症。1995; 60：812-815。