Mapping the Angiotensin II-TGFB-Integrin signaling triad to reveal therapeutic targets in aortic aneurysm

绘制血管紧张素 II-TGFB-整合素信号三联体图谱以揭示主动脉瘤的治疗靶点

• 批准号: 9274098
• 负责人: Sarah J Parker
• 金额: $ 17.1万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274098
• 关键词: Adhesions; Affect; Aneurysm; Angiotensin II; Aorta; Aortic Aneurysm; Apoptosis; Apoptotic; Area; Attenuated; Award; Binding; Biological; Biological Markers; Biology; Blood Vessels; California; Cardiovascular Physiology; Cardiovascular system; Cell physiology; Cereals; Cessation of life; Characteristics; Clinical; Clinical Research; Collaborations; Communication; Complement Factor B; Complex; Connective Tissue Diseases; Cytoskeletal Modeling; Cytoskeleton; Data; Data Set; Development; Disease; Dissection; Doctor of Philosophy; Elastin; Elements; Environment; Etiology; Event; Excision; Extracellular Matrix; FBN1; Fellowship; Film; Fostering; Functional disorder; Generations; Genes; Genetic; Genetic study; Goals; Growth; Hereditary Disease; Impairment; In Situ; In Vitro; Informatics; Institution; Integrin beta3; Integrins; Intervention; Knock-in Mouse; Knock-out; Laboratories; Lead; Leadership; Ligands; Link; Losartan; MADH2 gene; MAPK3 gene; Malignant Neoplasms; Maps; Marfan Syndrome; Mass Spectrum Analysis; Mechanics; Medial; Mediating; Mediator of activation protein; Medical Genetics; Medical center; Mentors; Mentorship; Molecular; Mus; Muscle Cells; Mutation; Operative Surgical Procedures; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patient Care; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Physiological; Physiology; Postdoctoral Fellow; Principal Investigator; Proteomics; Receptor Cross-Talk; Receptor Signaling; Receptor, Angiotensin, Type 1; Research; Research Institute; Research Personnel; Rupture; Signal Transduction; Smooth Muscle Myocytes; Stimulus; TGFB1 gene; Techniques; Technology; Testing; Thinness; Thoracic Aortic Aneurysm; Tissues; Training; Transforming Growth Factors; Translating; Triad Acrylic Resin; United States; Universities; Validation; Vascular Smooth Muscle; Wisconsin; arrestin 2; base; beta-arrestin; career; cell type; cohesion; design; experimental study; extracellular; high risk; in vitro Model; in vivo; insight; mechanical properties; medical schools; mouse model; muscle engineering; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; prevent; programs; research clinical testing; skills; success; therapeutic candidate; therapeutic target; transmission process

 DESCRIPTION (provided by applicant): PROJECT SUMMARY Aortic aneurysm is a prevalent condition defined by excessive aortic growth and medial wall remodeling that can result in lethal dissection and rupture. Few effective pharmacological treatments exist for aneurysm, due in large part to an incomplete understanding of the mechanisms that underlie the disease. The goal of this proposal is to derive a more comprehensive understanding of the molecular events that belie thoracic aortic aneurysm progression, and in so doing identify and validate potential targets for novel pharmacological therapy. Preliminary in vitro and in vivo data indicate that interactions between angiotensin II, integrin, and transforming growth factor β (TGFβ) signaling are key molecular elements of aneurysm pathogenesis. The principal investigator, Dr. Sarah Parker, uses a genetic knock-in mouse model of Marfan syndrome (MFS) to study the context-dependent molecular mechanisms leading to dysregulated TGFβ signaling in thoracic aortic aneurysm. In the mentored phase of this proposal, Dr. Parker will use in vitro techniques to assess how of Integrin β3 (ITGβ3) overexpression, as occurs in MFS, impacts aspects of vascular smooth muscle cell physiology known to be altered in aortic aneurysm, and use novel mass spectrometry technologies (data independent acquisition MS) to identify pathogenic signaling components downstream of ITGβ3 that drive altered VSMC physiology (Aim 1). In the transition to the independent phase, Dr. Parker will identify how another signaling network, β-Arrestin 2 (βARR2) biased signaling by the Angiotensin II Type 1 Receptor (AT1R), contributes to dysregulated TGFβ signaling and altered mechanical properties of VSMCs that occur during aneurysm in MFS (Aim 2). Finally, Dr. Parker will integrate the findings in Aims 1 and 2 to test a unifying hypothesis that altered matrix sensing by ITGβ3 contributes to βARR2 biased signaling by AT1R both in vitro as well as in vivo in MFS mice, and further determine whether pharmacological manipulation of ITGβ3 and/or βARR2-biased signaling can attenuate aneurysm progression in MFS (Aim 3). Dr. Parker received her Ph.D. in Physiology from the Medical College of Wisconsin (MCW). She has subsequently completed the first three and a half years of her Post Doctoral fellowship at Johns Hopkins University under the collaborative mentorship of Dr. Harry (Hal) Dietz, a renowned clinician and expert in the medical genetics of connective tissue disorders and aortic aneurysm, and Dr. Jennifer Van Eyk, a premier expert in clinical cardiovascular proteomics. Building upon her established expertise in cardiovascular physiology and mass spectrometry-based proteomic techniques, this K99/R00 award will allow Dr. Parker to (1) develop informatics and computational skills for the analysis and interpretation of complex molecular data sets, (2) in collaboration with Dr. Megan McCain at the University of Southern California, develop an in vitro model to independently modify matrix components, smooth muscle cell types, and soluble extracellular factors in order to study contractile physiology in smooth muscle cells, (3) continue to build expertise in the vascular biology of the aorta and (4) strengthen her communication, mentoring, management, and leadership skills to prepare for success as an independent biomedical researcher. Dr. Parker will complete the mentored phase of this award at Cedars-Sinai Medical Center (CSMC), where her primary mentor, Dr. Van Eyk, has recently moved her laboratory to become the director of the Advanced Clinical Biosystems Research Institute. Dr. Parker has enlisted an impressive team of mentors and advisors both local to Cedars Sinai (Dr. Jennifer Van Eyk, Dr. Moshe Arditi, Dr. Ben Berman, Dr. Ken Bernstein) and at external institutions (Dr. Hal Dietz, Dr. John Yates, and Dr. Megan McCain) to facilitate her scientific and personal development. The clinical research environments fostered by the institutions where Dr. Parker has been trained (Johns Hopkins, MCW) and will continue her training (CSMC) provide ideal settings to facilitate her long-term career goal to elucidate context-dependent, pathological signaling events in situ and connect them with the altered cellular, tissue, and organ physiology characteristic of disease pathogenesis. Dr. Parker will first focus her approach on the specific etiological mechanisms that drive ascending aortic aneurysm, and intends to eventually expand her research into other areas of cardiovascular biology where the full complexity of external and internal molecular context must be understood in order to best predict the cause-and-effect relationships between cell signaling and pathophysiology. To achieve this goal, Dr. Parker intends to bridge focused mass spectrometry-based discovery workflows with careful biological validation and the pre-clinical testing of novel therapeutic candidates that will be used to treat specific pathologies. This award will be fundamental in supporting Dr. Parker to build the framework for a research program that will achieve her career goals. Furthermore, by completing the aims of this proposal Dr. Parker will make a significant contribution toward the development of new treatments that will prevent the debilitating consequences of aortic aneurysm.

 描述（由适用提供）：项目摘要主动脉瘤是由主动脉生长过多和培养基壁重塑所定义的普遍状况，可能导致致命的解剖和破裂。动脉瘤几乎没有有效的药物治疗，这在很大程度上是由于对疾病构成的机制的不完全理解。该提案的目的是对相信胸部主动脉瘤进展的分子事件有更全面的了解，并因此确定并验证了新型药理治疗的潜在靶标。初步体外和体内数据 表明血管紧张素II，整联蛋白和转化生长因子β（TGFβ）信号传导之间的相互作用是动脉瘤发病机理的关键分子元素。首席研究者莎拉·帕克（Sarah Parker）博士使用Marfan综合征（MFS）的遗传敲门小鼠模型研究了依赖上下文依赖性的分子机制，从而导致胸动脉瘤中TGFβ信号失调。 In the mended phase of this proposal, Dr. Parker will use in vitro techniques to assess how of Integrin β3 (ITGβ3) overexpression, as occurs in MFS, impacts aspects of vascular smooth muscle cell physiology known to be altered in aortic aneurysm, and use novel mass spectrometry technologies (data independent acquisition MS) to identify pathogenic signaling components downstream of ITGβ3 that drive改变了VSMC生理学（AIM 1）。在向独立阶段的过渡中，帕克博士将确定另一个信号网络β-arrestin 2（βArr2）如何通过血管紧张素II类型1受体（AT1R）偏置信号传导，导致TGFβ信号传导失调，并改变了MFS中AneurysM（Aneurysm）在MFS中发生的VSMC的机械性能改变。最后，帕克博士将在目标1和2中整合发现的结果，以测试一个统一的假设，即ITGβ3改变矩阵传感会导致βARR2在MFS小鼠的体外以及体内均偏置信号传导，并进一步确定ITGβ3和/或βar的药理操纵是否能够对iTGβ3和/β-biials的药理操纵构成。 3）。帕克博士获得博士学位威斯康星州医学院（MCW）的生理学博士学位。 She has subsequently completed the first three and a half years of her Post Doctoral fellowship at Johns Hopkins University under the Collaborative Mentorship of Dr. Harry (Hal) Dietz, a renowned clinical and expert in the medical genetics of connective tissue disorders and aortic aneurysm, and Dr. Jennifer Van Eyk, a premier expert in clinical cardiovascular proteomics. Building upon her established expertise in cardiovascular physiology and mass spectrometry-based proteomic techniques, this K99/R00 award will allow Dr. Parker to (1) develop informatives and computational skills for the analysis and interpretation of complex molecular data sets, (2) in collaboration with Dr. Megan McCain at the University of Southern California, develop an in vitro model to independently modify matrix components, smooth muscle cell types, and solid （3）为了研究平滑肌细胞中的收缩生理的细胞外因素，（3）继续在主动脉的血管生物学方面建立专业知识，（4）（4）增强她的沟通，心理，管理和领导能力，以准备作为独立生物医学研究人员成功的成功。 Parker博士将在Cedars-Sinai医疗中心（CSMC）完成该奖项的Mendor阶段，她的主要导师Van Eyk博士最近搬迁了她的实验室，成为高级临床生物系统研究所的主任。帕克博士招募了一支令人印象深刻的保姆和顾问团队，包括锡达尔·西奈（Cedars Sinai）（詹妮弗·范·艾克（Jennifer Van Eyk）博士，博士Moshe Arditi博士，Ben Berman博士，Ken Bernstein博士）和外部机构（Hal Dietz博士，John Dietz博士，John Yates博士，John Yates和Megan McCain博士），以促进她的科学和个人发展。帕克博士接受了培训（Johns Hopkins，MCW）的机构培养的临床研究环境，并将继续她的培训（CSMC）提供理想的环境，以促进她的长期职业目标，以阐明上下文依赖于情境，病理信号事件，并与疾病生理学的细胞，组织和器官生理学的疾病生理学特征相关联。帕克博士将首先将其方法集中在推动主动脉瘤上升的特定病因机制上，并打算最终将其研究扩展到心血管生物学的其他领域，其中必须理解外部和内部分子环境的全部复杂性，以便最好地预测细胞信号传导和病理生理学之间的因果关系。为了实现这一目标，帕克博士打算通过仔细的生物学验证桥接基于质谱的质谱工作流以及将用于治疗特定病理学的新型治疗候选者的临床前测试。该奖项将是支持帕克博士建立将实现其职业目标的研究计划的框架的基础。此外，通过完成该提案的目标，帕克博士将为开发新疗法做出重大贡献，以防止主动脉瘤的衰弱后果。