Notch3 signaling in the pathogenesis of hemangioma

Notch3信号在血管瘤发病机制中的作用

• 批准号: 7871534
• 负责人: June Kar-ming Wu
• 金额: $ 13.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871534
• 关键词: Address; Adult; Advisory Committees; Affect; Amblyopia; Animal Model; Award; Basic Science; Behavior; Benign; Biological Assay; Biometry; Blindness; Blood Vessels; CSPG4 gene; Cell Differentiation process; Cell physiology; Cells; Characteristics; Child; Childhood; Clinical; Clinical Research; Clinical Trials Design; Dermal; Desmin; Development; Disease; Endothelial Cells; Endothelium; Environment; Equipment; FDA approved; Face; Gene Proteins; Genes; Hemangioma; Hemorrhage; Hospitals; Human; Immunodeficient Mouse; Infant; K-Series Research Career Programs; Laboratories; Learning; Lesion; Life; Life Cycle Stages; MCAM gene; Maintenance; Mentorship; Molecular Biology; Morbidity - disease rate; Morphology; NCI Center for Cancer Research; New York; Operative Surgical Procedures; Pain; Pathogenesis; Patients; Pattern; Pediatric Hospitals; Pericytes; Phase; Phenotype; Plastic Surgeon; Play; Population; Positioning Attribute; Presbyterian Church; Prevention; Proliferating; Regulation; Research; Resected; Risk; Role; Scientist; Secure; Signal Transduction; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Source; Specimen; Stem cells; Strawberry nevus; Stroke; Syndrome; Testing; Time; Tissues; Training; Ulcer; Universities; Work; angiogenesis; base; bench to bedside; cell behavior; cell type; design; improved; infancy; insight; interest; malformation; meetings; member; migration; notch protein; prevent; protein expression; public health relevance; respiratory; responsible research conduct; small hairpin RNA; symposium; therapeutic target; tumor; vasculogenesis

DESCRIPTION (provided by applicant): Candidate: I am a pediatric plastic surgeon with an interest in Vascular Anomalies, and a member of Columbia University's multi-disciplinary Vascular Anomalies Group. My clinical expertise includes treating children, affected by hemangiomas and vascular malformations, which allows access to resected clinical specimens that can be used for research. I am interested in studying normal and abnormal vasculogenesis and angiogenesis in hemangiomas, specifically Notch signaling in hemangiomas, since Notch is known to play a role in vasculogenesis and angiogenesis. I was able to secure support and mentorship from Dr. Jan Kitajewski, a vascular biologist studying Notch and Dr. Joyce Bischoff, a hemangioma expert. With their support and guidance, I was able to show, for the first time, that Notch genes were expressed in hemangiomas in an intriguing pattern. As a clinician who specializes in Vascular Anomalies, I am in a unique position to observe the clinical behavior of these lesions and bring research ideas to fruition through a Career Development Award, i.e., from bedside to the bench, and to design and conduct basic science research independently. In addition, if awarded, I will also plan to attend classes on conducting responsible clinical research and biostatistics, so that I can apply what I learn in the laboratory-from bench to bedside-to design clinical trials to improve treatment options for children with problematic hemangiomas. Environment: Columbia University and New York Presbyterian Hospital has a free-standing Children's Hospital and specializes in treating the pediatric population in a variety of diseases and conditions. With our Vascular Anomalies Group, we have a steady patient referral base. Moreover, I have research space both with the Department of Surgery, as well as space with Dr. Kitajewski's laboratory in the Irving Cancer Research Center. Dr. Kitajewski's laboratory has the necessary equipment and facilities necessary to conduct Notch signaling research. Moreover, there will be ample opportunities to interact with graduate and post-graduate research fellows in his laboratory, both in formal laboratory meetings and informally at the bench. Dr. Kitajewski's laboratory is physically connected to Drs. Kandel and Yamashiro's laboratory, who are on my advisory committee. Columbia University holds many seminars and conferences, from molecular biology to responsible research conduct. Therefore, Columbia University is the ideal place to train as a clinician scientist. Research: Infantile hemangiomas (IHs) are the most common benign tumors of infancy. They have a unique life cycle: from rapid proliferation followed by involution. Despite being "benign" lesions, they can cause significant, possibly irreversible, morbidity during proliferation, including life-threatening respiratory compromise, blindness, hemorrhage, and ulceration. Infants with large, segmental facial hemangiomas as part of the PHACES syndrome are at risk for strokes. There is currently no FDA-approved treatment for problematic IHs, in part due to limited understanding of the origin and regulation of IHs, and lack of an animal model until recently. Therefore, development of targeted therapy for problematic hemangiomas has been hampered. Recent studies have shown that the hemangioma stem cell (HemSC) as the origin of hemangiomas, a highly proliferative cell, which then differentiates to an endothelial fate (HemEC)(Khan, Boscolo et al. 2008). Other cell types are also known to be present in hemangiomas, including pericytes, which have never been isolated from a hemangioma(Boscolo and Bischoff 2009) but may arise from HemSC as well. It is known that endothelial cell and pericyte interactions are vital to formation of blood vessels. Work in our laboratory has shown that Notch3 is expressed in HemSCs, but not HemECs nor human dermal microvascular endothelial cells (HDMECs). Notch3, however, is known to be expressed by perictyes and play a role in blood vessel formation via Notch3 regulation(Liu, Kennard et al. 2009). Our hypothesis is that proliferation and involution in hemangiomas is controlled by Notch3 activity, and Notch3 expression is not required or must be turned off for HemSC to differentiate into HemEC. We hypothesize that Notch3 also play a role in the differentiation of HemSC to perictyes in hemangiomas. We have 3 specific aims to address these questions. The first will focus on the role of Notch3 in helping to maintain HemSCs in their capacity to proliferate and grow. The second aim to isolate and characterize Notch3-positive pericytes in hemangiomas. Finally, we aim to study the effects of activating Notch3 activity in HemEC, to see whether we can force the HemEC to become more like a HemSC or a pericyte. Boscolo, E. and J. Bischoff (2009). "Vasculogenesis in infantile hemangioma." Angiogenesis. Khan, Z. A., E. Boscolo, et al. (2008). "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice." J Clin Invest. Liu, H., S. Kennard, et al. (2009). "NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1." Circ Res 104(4): 466-75. PUBLIC HEALTH RELEVANCE: This proposal will study the regulation of HemSC and HemEC by NOTCH3 in hemangiomas, potentially giving us a therapeutic target for treating proliferating, problematic hemangiomas. Moreover, it will help provide insights to normal and abnormal blood vessel formation, and the interaction between a stem cell, and endothelial cell, and a pericyte in formation of blood vessels.

描述（由申请人提供）：候选人：我是一名对血管异常感兴趣的儿科整形外科医生，并且是哥伦比亚大学多学科血管异常组的成员。我的临床专业知识包括治疗受血管瘤和血管畸形影响的儿童，允许访问可用于研究的切除的临床标本。我有兴趣研究血管瘤中血管瘤中的正常和异常血管生成和血管生成，特别是血管瘤中的Notch信号传导，因为已知Notch在血管生成和血管生成中起着作用。我能够获得研究Notch的血管生物学家Jan Kitajewski博士和血管瘤专家Joyce Bischoff博士的支持和指导。在他们的支持和指导下，我首次能够以有趣的模式在血管瘤中表达Notch基因。作为专门从事血管异常的临床医生，我处于独特的位置，可以通过职业发展奖，即从床头到板凳，并独立设计和进行基础科学研究，从而遵守这些病变的临床行为，并通过职业发展奖实现研究思想。此外，如果获得授予，我还计划参加进行负责任的临床研究和生物统计学的课程，以便我可以将我在实验室长凳上学习的知识应用于床边设计临床试验，以改善有问题的血管瘤儿童的治疗选择。环境：哥伦比亚大学和纽约长老会医院拥有一家独立的儿童医院，专门治疗各种疾病和疾病的小儿人群。借助我们的血管异常组，我们具有稳定的患者转诊基础。此外，我在欧文癌症研究中心的Kitajewski博士的实验室中都有研究空间以及与Kitajewski博士的空间。 Kitajewski博士的实验室拥有进行Notch信号研究所需的必要设备和设施。此外，在正式的实验室会议和非正式的替补席上，将有足够的机会与他的实验室中的研究生和研究生研究人员进行互动。 Kitajewski博士的实验室与Drs的物理联系。坎德尔（Kandel）和亚马什罗（Yamashiro）的实验室，是我的咨询委员会。哥伦比亚大学举办了许多研讨会和会议，从分子生物学到负责任的研究行为。因此，哥伦比亚大学是临床科学家培训的理想场所。研究：婴儿血管瘤（IHS）是婴儿期最常见的良性肿瘤。他们有一个独特的生命周期：从快速增殖，然后是涉及。尽管是“良性”病变，但它们仍会在增殖过程中引起明显的，可能是不可逆的发病率，包括威胁生命的呼吸疾病，失明，出血和溃疡。具有大型的，分段的面部血管瘤作为鼻综合征的一部分的婴儿有中风的风险。目前，由于对IHS的起源和调节的理解有限，直到最近才缺乏FDA批准的有问题的IHS治疗方法，部分原因是由于有限。因此，有问题的血管瘤的靶向疗法受到阻碍。最近的研究表明，血管瘤干细胞（HEMSC）作为高度增殖性细胞血管瘤的起源，然后将其区分为内皮命运（Hemec）（Hemec）（Khan，Boscolo等，2008）。已知其他细胞类型也存在于血管瘤中，包括周细胞，这些细胞瘤从未从血管瘤中分离出来（Boscolo and Bischoff 2009），但也可能来自HEMSC。众所周知，内皮细胞和周细胞相互作用对于血管形成至关重要。我们的实验室的工作表明Notch3在HEMSC中表达，但没有人类皮肤微血管内皮细胞（HDMEC）。然而，Notch3是通过核细胞表达的，并通过Notch3调节在血管形成中发挥作用（Liu，Kennard等，2009）。我们的假设是，血管瘤中的增殖和参与受Notch3活性的控制，而Notch3表达不需要或必须关闭HEMSC才能分化为HEMEC。我们假设Notch3在HEMSC与血管瘤中的细胞菌的分化中也起着作用。我们有3个具体的目的来解决这些问题。第一个将重点关注Notch3在帮助维持HEMSC的作用，以增殖和成长的能力。隔离和表征血管瘤中Notch3阳性周细胞的第二个目的。最后，我们旨在研究Hemec中激活Notch3活性的影响，以了解我们是否可以迫使Hemec变得更像Hemsc或周细胞。 Boscolo，E。和J. Bischoff（2009）。 “婴儿血管瘤中的血管生成。”血管生成。 Khan，Z。A.，E。Boscolo等。 （2008）。 “多能干细胞概括了免疫缺陷小鼠中的人类婴儿血管瘤。” J Clin Invest。 Liu，H.，S。Kennard等。 （2009）。 “ Notch3的表达是通过需要进行内皮表达的JAGGED1的自动调节环在壁画细胞中诱导的。” Circ Res 104（4）：466-75。 公共卫生相关性：该提案将研究Notch3在血管瘤中对HEMSC和HEMEC的调节，这可能为我们提供了治疗增生的有问题的血管瘤的治疗靶标。此外，它将有助于为正常和异常的血管形成，干细胞和内皮细胞之间的相互作用以及血管形成的周围的洞察力提供见解。