BRITE Relaunch: Examining the Role of Mechanotransduction in Smooth Muscle Cell Phenotype Modulation

BRITE 重新推出：检查机械转导在平滑肌细胞表型调节中的作用

• 批准号: 2135589
• 负责人: Chartrisa Hendrix
• 金额: $ 55.99万
• 依托单位: Mississippi State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2135589&HistoricalAwards=false
• 关键词: BRITE; Relaunch; Examining; Role; Mechanotransduction

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).The vascular smooth muscle cells (VSMCs) that make up one of the layers of arteries exhibit two distinct types: contractile and synthetic. Contractile VSMCs regulate blood pressure in the artery by contracting or relaxing. However, they can revert into the synthetic type in response to an injury to the blood vessel. Synthetic VSMCs are responsible for synthesis of replacement cells and secretion of substances that are needed for vessel healing. This Boosting Research Ideas for Transformative and Equitable Advances in Engineering (BRITE) Relaunch project has hypothesizes that a third type of VSMCs exists, and the change in the cells to this third type is caused by stretch within the vascular tissue. It is further hypothesized that this change to the third type of VSMC happens through a signaling pathway known as Wnt. Through this pathway, the VSMCs become bone-like cells and deposit mineral (calcium) into the arterial tissue that surrounds the cells, the extracellular matrix. The mechanical changes leading to this potential third phenotype are caused by hypertension, known as the silent killer. By understanding the signaling pathway associated with this change in the behavior of VSMCs, future research can be supported to develop targeted therapeutics to treat vascular calcification (i.e., hardening of the arteries) at the cellular and molecular level. This work could drive future research that will reduce the severity of heart disease complications experienced by patients and reduce the costs of treating high-risk patients. This project will also increase the participation of students from underrepresented groups in research -- in particular, first-generation, low-income students. This project will advance knowledge by investigating the hypothesis that the continued plasticity of VSMCs to a third phenotype is caused by mechanical strain activating the canonical Wnt signaling pathway. An in vitro vascular calcification model will be used to examine the role of mechanotransduction in VSMC phenotype changes. This project will: 1) investigate the activation of a Wnt signaling pathway in synthetic VSMCs; 2) examine the impact of surface mechanics on the activation of phenotypic modulation via the Wnt signaling pathway; and 3) examine the phenotypic modulation of VSMCs under mechanical strain. This mechanical loading will mimic the physiological exposure of VSMCs to increased stretch due to hypertension, which is then hypothesized to cause a response within the tissue to increase its stiffness through calcification and return the range of strains to a tissue-specific homeostatic level. This mechanical transduction response is known to occur in most biological tissues, including in bone.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项的全部或部分资金根据《2021 年美国救援计划法案》（公法 117-2）提供。构成动脉层的血管平滑肌细胞 (VSMC) 有两种不同的类型：收缩型和合成型。收缩性 VSMC 通过收缩或舒张来调节动脉血压。然而，当血管受伤时，它们可以恢复为合成类型。合成 VSMC 负责合成替代细胞并分泌血管愈合所需的物质。这个促进工程变革和公平进步的研究理念 (BRITE) 重新启动项目假设存在第三种类型的 VSMC，并且细胞向第三种类型的变化是由血管组织内的拉伸引起的。进一步假设第三种 VSMC 的这种变化是通过称为 Wnt 的信号通路发生的。 通过这一途径，VSMC 变成骨样细胞，并将矿物质（钙）沉积到细胞周围的动脉组织（细胞外基质）中。导致这种潜在第三种表型的机械变化是由被称为“沉默杀手”的高血压引起的。通过了解与 VSMC 行为变化相关的信号通路，可以支持未来的研究开发靶向疗法，在细胞和分子水平上治疗血管钙化（即动脉硬化）。这项工作可以推动未来的研究，降低患者心脏病并发症的严重程度，并降低治疗高危患者的成本。该项目还将增加代表性不足群体的学生——特别是第一代低收入学生——的参与。该项目将通过研究以下假设来推进知识的发展：VSMC 向第三种表型的持续可塑性是由激活经典 Wnt 信号通路的机械应变引起的。体外血管钙化模型将用于检查机械转导在 VSMC 表型变化中的作用。该项目将：1）研究合成 VSMC 中 Wnt 信号通路的激活； 2) 检查表面力学对通过Wnt信号通路激活表型调节的影响； 3) 检查机械应变下 VSMC 的表型调节。 这种机械负荷将模拟 VSMC 因高血压而增加的生理暴露，然后假设这会引起组织内的反应，通过钙化增加其硬度，并使应变范围恢复到组织特异性稳态水平。 众所周知，这种机械转导反应发生在大多数生物组织中，包括骨骼中。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。