The Role of TGF-beta Activation and Signaling in Aortic Stenosis Progression

TGF-β 激活和信号转导在主动脉瓣狭窄进展中的作用

• 批准号: 10570994
• 负责人: Jasimuddin Ahamed
• 金额: $ 51.74万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570994
• 关键词: Affect; Age Years; American; Aortic Valve Stenosis; Biological Assay; Biological Markers; Blood Platelets; Cardiovascular Diseases; Cause of Death; Cell secretion; Cells; Cessation of life; Clinical; Clinical Research; Collagen; Data; Development; Disease; Disulfides; Dose; Elderly; Endothelial Cells; Fibrosis; Future; Goals; Growth Factor; Heart; Heart failure; Human; In Vitro; Isolectin; KAI1 gene; Knock-in Mouse; Low Density Lipoprotein Receptor; Macrophage; Measures; Mediating; Mesenchymal; Methods; Modeling; Mus; Myofibroblast; Organ; Outcome; Pathogenesis; Pathologic; Patients; Plasma; Play; Population; Prevention therapy; Procedures; Process; Production; Prognosis; Protein Disulfide Isomerase; Publishing; Research; Risk; Risk Factors; Role; Sampling; Signal Transduction; Source; Sulfhydryl Compounds; Techniques; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Ultrasonography; Work; aortic valve; blood pump; cell type; cytokine; drug development; imaging modality; improved; in vivo; innovation; mouse model; mutant; new therapeutic target; novel; novel diagnostics; oxidation; pharmacologic; potential biomarker; pre-clinical assessment; prevent; profibrotic cytokine; prognostic; prospective; recruit; shear stress; small molecule inhibitor; valve replacement

PROJECT SUMMARY Aortic stenosis (AS) is a degenerative heart condition characterized by fibrosis and narrowing of the aortic valve. AS causes increased wall shear stress across the aortic valve, making the heart work harder to pump blood through the narrowed valve opening. These effects can cause heart failure and death. The only current treatment for AS is valve replacement, an invasive and risky procedure. Our long-term goal is to improve the understanding and treatment of fibrosis, which underlies AS. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that induces pathologic organ fibrosis in many disorders. Cells secrete latent (L)TGF-β1, and increased plasma levels of LTGF-β1 have been associated with AS in humans and in a mouse model of AS. We showed that wall shear stress can dramatically activate LTGF-β1 released from platelets in vitro. However, the mechanism of TGF-β1 activation in vivo and its signaling on valvular cells in AS remain poorly understood. The objective of this application is to determine the mechanism of LTGF-β1 activation in vivo and identify the cell types to which TGF- β1 signals, leading to their mesenchymal transition and subsequent AS progression. Platelets are the major source of plasma LTGF-β1, as they contain more than 100 times as much LTGF-β1 as other cell types, and our preliminary data show that platelets are physically attached to isolectin B4-positive valvular cells, presumably valvular endothelial cells (VEC) undergoing mesenchymal transition and giving rise to collagen-producing myofibroblasts in an AS mouse model. These results led to our central hypothesis that wall shear stress activates platelet-derived TGF-β1, which stimulates isolectin B4-positive cells (VECs and/or macrophages) to undergo mesenchymal transition, thereby producing excessive collagen and leading to AS progression. Furthermore, TGF-β1 may represent a previously unrealized clinical indicator of AS progression. We propose the following Specific Aims: (1) Determine whether wall shear stress activates LTGF-β1 in vivo; and (2) Determine whether TGF-β1 signaling in valvular cells leads to mesenchymal transition and AS progression. Our proposed studies will clarify the mechanism of TGF-β1 activation in vivo and the cell types on which TGF-β signals, leading to mesenchymal transition and AS progression. We will use innovative, sensitive techniques to evaluate AS development in mouse models and to measure active TGF-β1 levels in plasma samples from AS patients. Furthermore, the proposed research will explore the mitigation of AS progression using two low-dose small-molecule inhibitors of TGF-β1 activation and signaling. Our pre-clinical assessment of TGF-β1 activation and signaling in AS patient samples will be crucial for prospective clinical studies on the use of TGF-β1 as a biomarker of AS. Overall, our proposed studies will provide a more complete understanding of the role of TGF-β1 in AS, which may establish TGF-β1 as a novel target for drug development and a potential biomarker of AS and other fibrotic diseases.

项目摘要 主动脉狭窄（AS）是一种退化性心脏病，其特征是纤维化和主动脉瓣的变窄。作为 导致墙壁上的壁剪应力增加增加，使心脏更加努力地通过 狭窄的阀门。这些影响会导致心力衰竭和死亡。 AS唯一目前的治疗方法 阀门更换，一种侵入性和风险的程序。我们的长期目标是提高理解和 纤维化的处理，其基础为。转化生长因子-β1（TGF-β1）是一种多功能细胞因子， 在许多疾病中诱导病理器官纤维化。细胞秘密潜伏（L）TGF-β1，血浆水平升高 LTGF-β1的AS与AS和AS的小鼠模型有关。我们展示了墙上的剪切 应力可以显着激活体外血小板释放的LTGF-β1。但是，TGF-β1的机制 体内激活及其在瓣膜细胞上的信号传导仍然不足。这个目的 应用是在体内确定LTGF-β1激活的机制，并确定TGF-的细胞类型 β1信号导致其间充质转变，随后作为进展。血小板是主要来源 血浆LTGF-β1的含量是其他细胞类型的100倍以上的LTGF-β1，我们的初步 数据表明，血小板在物理上附着在分离蛋白B4阳性瓣膜细胞上，大概是瓣膜 内皮细胞（VEC）经历了间质转变并引起产生胶原蛋白的成肌纤维细胞 在AS鼠标模型中。这些结果导致了我们的中心假设，即壁剪应力激活了血小板来源 TGF-β1，刺激分离蛋白B4阳性细胞（VEC和/或巨噬细胞）进行间充质的细胞（VEC和/或巨噬细胞） 过渡，从而产生过多的胶原蛋白并导致进展。此外，TGF-β1可能 代表了先前未实现的临床指标。我们提出以下特定目标：（1） 确定壁剪应力是否在体内激活LTGF-β1； （2）确定TGF-β1是否在 瓣膜细胞导致间充质转变和进展。我们提出的研究将阐明 TGF-β1在体内激活的机理和TGF-β信号的细胞类型，导致间充质 过渡和进展。我们将使用创新，敏感的技术来评估作为发展 小鼠模型并测量来自患者血浆样品中的活性TGF-β1水平。此外， 拟议的研究将使用两种低剂量的小分子抑制剂来探讨AS进展的缓解措施 TGF-β1激活和信号传导。我们对TGF-β1激活和信号的临床前评估AS患者 样品对于使用TGF-β1作为AS的生物标志物的前瞻性临床研究至关重要。总体而言，我们的 拟议的研究将为TGF-β1在AS中的作用提供更完整的了解，这可能会确定 TGF-β1是药物发育的新靶标，也是AS和其他纤维化疾病的潜在生物标志物。

项目成果

Premortem Skin Biopsy Assessing Microthrombi, Interferon Type I Antiviral and Regulatory Proteins, and Complement Deposition Correlates with Coronavirus Disease 2019 Clinical Stage.

• DOI: 10.1016/j.ajpath.2022.05.006
• 发表时间: 2022-09
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Laurence, Jeffrey;Nuovo, Gerard;Racine-Brzostek, Sabrina E.;Seshadri, Madhav;Elhadad, Sonia;Crowson, Neil;Mulvey, J. Justin;Harp, Joanna;Ahamed, Jasimuddin;Magro, Cynthia
• 通讯作者: Magro, Cynthia

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches.

• DOI: 10.1172/jci161167
• 发表时间: 2022-08-01
• 期刊: The Journal of clinical investigation
• 作者: Ahamed J;Laurence J
• 通讯作者: Laurence J