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: 2422794
• 负责人: Chartrisa Hendrix
• 金额: $ 55.99万
• 依托单位: University of Cincinnati Main Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2422794&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.

该奖项是根据2021年《美国救援计划法》（公法117-2）全部或部分资助的。构成动脉层之一的血管平滑肌细胞（VSMC）表现出两种不同的类型：收缩和合成。收缩VSMC通过收缩或放松来调节动脉中的血压。但是，它们可以响应血管损伤而恢复合成类型。合成VSMC负责替换细胞的合成以及血管愈合所需的物质的分泌。这一促进了工程（BRITE）重新推出项目的变革性和公平进步的研究思想假设存在第三种VSMC，并且细胞向第三种类型的变化是由血管组织内部伸展引起的。进一步假设，这种变为第三种VSMC的变化是通过称为Wnt的信号通路发生的。 通过这一途径，VSMC成为骨状细胞，并沉积矿物（钙）到围绕细胞（细胞外基质）的动脉组织中。导致该潜在第三个表型的机械变化是由高血压引起的，被称为沉默杀手。通过了解与VSMC行为变化相关的信号传导途径，可以支持未来的研究，以开发有针对性的治疗剂来治疗细胞和分子水平的血管钙化（即动脉硬化）。这项工作可能会推动未来的研究，从而减少患者心脏病并发症的严重性，并降低治疗高危患者的成本。该项目还将增加代表性不足小组研究的学生的参与，特别是第一代低收入学生。该项目将通过研究以下假设，即VSMC对第三个表型的持续可塑性是由激活规范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制的影响； 3）检查机械应变下VSMC的表型调节。 这种机械负荷将模仿VSMC的生理暴露，从而增加了由于高血压而增加的拉伸，然后假设这会导致组织内的反应，从而通过钙化增加其刚度，并将菌株的范围返回到组织特异性体内平衡水平。 已知这种机械转导响应在大多数生物组织中都发生，包括骨骼。该奖项反映了NSF的法定任务，并且使用基金会的知识分子优点和更广泛的影响审查标准，被认为值得通过评估来获得支持。