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）： 项目摘要 主动脉瘤是一种常见疾病，其特征是主动脉过度生长和内壁重塑，可导致致命的夹层和破裂。对于动脉瘤，目前几乎没有有效的药物治疗方法，这在很大程度上是由于对该疾病的机制了解不完全。该提案的目标是更全面地了解掩盖胸主动脉瘤进展的分子事件，并在此过程中确定和验证新型药物治疗的潜在靶点。初步体外和体内数据 表明血管紧张素 II、整合素和转化生长因子 β (TGFβ) 信号之间的相互作用是动脉瘤发病机制的关键分子要素。首席研究员 Sarah Parker 博士使用马凡综合征 (MFS) 基因敲入小鼠模型来研究导致胸主动脉瘤中 TGFβ 信号失调的背景依赖性分子机制。在该提案的指导阶段，Parker 博士将使用体外技术来评估整合素 β3 (ITGβ3) 过度表达（如 MFS 中发生的情况）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的各个方面，并使用新型质谱技术（数据独立采集 MS）来识别驱动 ITGβ3 下游的致病信号成分 改变 VSMC 生理学（目标 1）。在过渡到独立阶段时，Parker 博士将确定另一个信号网络，即血管紧张素 II 1 型受体 (AT1R) 偏向的 β-Arrestin 2 (βARR2) 信号传导，如何导致 MFS 动脉瘤期间发生的 TGFβ 信号失调和 VSMC 的机械特性改变（目标 2）。最后，Parker 博士将整合目标 1 和 2 中的发现，以测试一个统一的假设，即 ITGβ3 改变的基质传感有助于 MFS 小鼠体外和体内 AT1R 的 βARR2 偏向信号传导，并进一步确定 ITGβ3 和/或 βARR2 偏向信号传导的药理操作是否可以减弱 MFS 中的动脉瘤进展（Aim 3）。帕克博士获得博士学位。威斯康星医学院 (MCW) 生理学博士学位。随后，她在结缔组织疾病和主动脉瘤医学遗传学著名临床医生和专家 Harry (Hal) Dietz 博士和临床心血管蛋白质组学顶级专家 Jennifer Van Eyk 博士的合作指导下，完成了约翰霍普金斯大学前三年半的博士后研究。基于她在心血管生理学和基于质谱的蛋白质组学技术方面的专业知识，Parker 博士将能够 (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，开发一个体外模型来独立修改基质成分、平滑肌细胞类型，以及 可溶性细胞外因子，以研究平滑肌细胞的收缩生理学，(3) 继续积累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，为作为一名独立生物医学研究员的成功做好准备。 Parker 博士将在 Cedars-Sinai 医疗中心 (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搬到了该中心，成为高级临床生物系统研究所的主任。 Parker 博士招募了一支令人印象深刻的导师和顾问团队，其中包括 Cedars Sinai 当地的导师和顾问（Jennifer Van Eyk 博士、Moshe 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。 Parker 博士接受过培训的机构（约翰·霍普金斯大学、MCW）和将继续接受培训的机构（CSMC）所营造的临床研究环境为促进她的长期职业目标提供了理想的环境，即阐明背景依赖性的原位病理信号事件，并将它们与疾病发病机制改变的细胞、组织和器官生理学特征联系起来。 Parker 博士将首先将她的方法集中在驱动升主动脉瘤的特定病因机制上，并打算最终将她的研究扩展到心血管生物学的其他领域，在这些领域中，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，帕克博士打算将基于质谱的重点发现工作流程与仔细的生物学验证和用于治疗特定病理的新型候选治疗药物的临床前测试结合起来。该奖项对于支持帕克博士构建实现其职业目标的研究项目框架至关重要。此外，通过完成该提案的目标，帕克博士将为开发新的治疗方法做出重大贡献，以防止主动脉瘤造成的衰弱后果。