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(由申请人提供)：主动脉瘤是一种常见的疾病，以过度的主动脉生长和内侧壁重构为特征，可导致致命的夹层和破裂。目前对动脉瘤的有效药物治疗很少，这在很大程度上是由于对疾病基础机制的不完全了解。这项建议的目的是为了更全面地了解胸主动脉瘤进展的分子事件，从而确定和验证新的药物治疗的潜在靶点。体内外数据的初步研究 提示血管紧张素II、整合素和转化生长因子β(转化生长因子β)信号之间的相互作用是动脉瘤发病的关键分子因素。首席研究员Sarah Parker博士利用马凡综合征(MFS)的基因敲入小鼠模型，研究了导致胸主动脉瘤转化生长因子β信号异常的上下文相关分子机制。在这项建议的指导阶段，Parker博士将使用体外技术来评估整合素组蛋白β3(Itgβ3)的过度表达如何影响已知在主动脉瘤中发生改变的血管平滑肌细胞生理学方面，并使用新的质谱学技术(数据独立采集MS)来识别Itgβ3下游驱动VSMC生理学改变的致病信号成分(目标1)。在向独立阶段的过渡中，Parker博士将确定另一个信号网络，血管紧张素II 1型受体(AT1R)偏向的β-arrestin 2(AT1R)信号网络如何促进ββ信号的失调以及在MFS动脉瘤期间发生的VSMCs的机械特性改变(AIM 2)。最后，Parker博士将整合AIMS 1和AIMS 2中的研究结果，以检验一个统一的假设，即在体外和体内，ITGβ3改变基质感知有助于AT1R偏向ββ的信号转导，并进一步确定对ItG ARR2 3和/或βARR2偏向信号的药理操作是否可以延缓MFS的动脉瘤进展(AIM 3)。帕克博士在威斯康星医学院(MCW)获得生理学博士学位。随后，在结缔组织疾病和主动脉瘤的医学遗传学方面的著名临床医生和医学遗传学专家Harry(Hal)Dietz博士和临床心血管蛋白质组学的首屈一指的专家Jennifer Van Eyk博士的合作指导下，她在约翰霍普金斯大学完成了头三年半的博士后研究。基于她在心血管生理学和基于质谱学的蛋白质组学技术方面的成熟专业知识，这项K99/R00奖将使Parker博士能够(1)开发用于分析和解释复杂分子数据集的信息学和计算技能，(2)与南加州大学的Megan McCain博士合作，开发独立修改基质成分、平滑肌细胞类型和可溶性细胞外因子的体外模型，以便研究平滑肌细胞的收缩生理学，(3)继续建立主动脉血管生物学方面的专业知识，(4)加强她的沟通、指导、管理、和领导技能，为成为一名独立的生物医学研究人员做好准备。帕克博士将在锡达斯-西奈医学中心(CSMC)完成该奖项的指导阶段，她的主要导师Van Eyk博士最近将她的实验室转移到高级临床生物系统研究所担任主任。Parker博士招募了一支令人印象深刻的导师和顾问团队，他们来自Cedars Sinai本地(Jennifer Van Eyk博士、Mohe Arditi博士、Ben Berman博士、Ken Bernstein博士)和外部机构(Hal Dietz博士、John Yates博士和Megan McCain博士)，以促进她的科学和个人发展。帕克博士所在的机构(约翰·霍普金斯大学，MCW)培养的临床研究环境为她提供了理想的环境，帮助她实现长期的职业目标，即在原位阐明上下文相关的病理信号事件，并将它们与疾病发病机制中改变的细胞、组织和器官生理学特征联系起来。帕克博士将首先将她的研究重点放在导致升主动脉瘤的具体病因机制上，并打算最终将她的研究扩展到心血管生物学的其他领域，在这些领域，必须了解外部和内部分子背景的全部复杂性，以便最好地预测细胞信号和病理生理学之间的因果关系。为了实现这一目标，帕克博士打算将基于质谱学的集中发现工作流程与仔细的生物学验证和将用于治疗特定病理的新型候选治疗药物的临床前测试联系起来。这一奖项将是支持帕克博士为实现她的职业目标的研究计划建立框架的基础。此外，通过完成这项建议的目标，帕克博士将为开发新的治疗方法做出重大贡献，这些治疗方法将防止主动脉瘤造成的令人衰弱的后果。