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.

项目概要 主动脉瓣狭窄 (AS) 是一种退行性心脏疾病，其特征是主动脉瓣纤维化和狭窄。 导致主动脉瓣壁剪切应力增加，使心脏更努力地泵血 瓣膜开口变窄，这些影响会导致心力衰竭和死亡。目前治疗 AS 的唯一方法是。 瓣膜置换术是一种侵入性且有风险的手术，我们的长期目标是提高对瓣膜置换术的理解和认识。 纤维化的治疗是 AS 的基础，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性器官纤维化，细胞分泌潜在的 (L)TGF-β1，并增加血浆水平。 在人类和小鼠 AS 模型中，LTGF-β1 的表达与 AS 相关。 体外应激可显着激活血小板释放的LTGF-β1，但TGF-β1的作用机制尚不清楚。 AS 体内的激活及其对瓣膜细胞的信号传导仍知之甚少。 应用是确定 LTGF-β1 体内激活机制并鉴定 TGF-β1 作用的细胞类型 导致间质转化和随后 AS 进展的 β1 信号是主要来源。 血浆 LTGF-β1 的含量，因为它们含有的 LTGF-β1 是其他细胞类型的 100 倍以上，我们初步 数据显示，血小板物理附着在异凝集素 B4 阳性瓣膜细胞上，推测为瓣膜细胞 内皮细胞 (VEC) 经历间质转化并产生产生胶原蛋白的肌成纤维细胞 在 AS 小鼠模型中，这些结果得出了我们的中心假设：壁剪切应力激活血小板衍生的。 TGF-β1，刺激异凝集素 B4 阳性细胞（VEC 和/或巨噬细胞）进行间充质转化 转变，从而产生过多的胶原蛋白并导致 AS 进展。此外，TGF-β1 可能会导致 AS 进展。 我们提出以下具体目标：（1） 确定壁剪切应力是否在体内激活LTGF-β1；以及（2）确定TGF-β1信号传导是否在体内； 我们提出的研究将阐明瓣膜细胞导致间质转化和 AS 进展。 体内 TGF-β1 激活机制以及 TGF-β 发出信号的细胞类型，导致间充质细胞 我们将使用创新、敏感的技术来评估 AS 的发展。 小鼠模型并测量 AS 患者血浆样本中的活性 TGF-β1 水平。 拟议的研究将探索使用两种低剂量小分子抑制剂缓解 AS 进展 TGF-β1 激活和信号传导。我们对 AS 患者 TGF-β1 激活和信号传导的临床前评估。 样本对于使用 TGF-β1 作为 AS 生物标志物的前瞻性临床研究至关重要。 拟议的研究将更全面地了解 TGF-β1 在 AS 中的作用，这可能会建立 TGF-β1 作为药物开发的新靶点以及 AS 和其他纤维化疾病的潜在生物标志物。

项目成果

Intervention in COVID-19 linked hypercoaguable states characterized by circuit thrombosis utilizing a direct thrombin inhibitor.

利用直接凝血酶抑制剂对以回路血栓形成为特征的 COVID-19 相关高凝状态进行干预。

• 发表时间: 2020-12
• 作者: Seshadri, Madhav;Ahamed, Jasimuddin;Laurence, Jeffrey
• 通讯作者: Laurence, Jeffrey

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

死前皮肤活检评估微血栓、I 型干扰素抗病毒和调节蛋白以及补体沉积与 2019 年冠状病毒病临床阶段的相关性。

• 发表时间: 2022-09
• 作者: Laurence, Jeffrey;Nuovo, Gerard;Racine;Seshadri, Madhav;Elhadad, Sonia;Crowson, A 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.

长期新冠内皮病：假设机制和潜在治疗方法。

• 发表时间: 2022-08-01
• 作者: Ahamed, Jasimuddin;Laurence, Jeffrey
• 通讯作者: Laurence, Jeffrey