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.

该奖项全部或部分由2021年美国救援计划法案（公法117-2）资助。构成动脉一层的血管平滑肌细胞（VSMCs）表现出两种不同的类型：收缩型和合成型。收缩性VSMC通过收缩或舒张来调节动脉中的血压。然而，它们可以在血管损伤时恢复为合成类型。合成VSMC负责合成替代细胞和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思路（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，第三种类型的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）存款到细胞周围的动脉组织（细胞外基质）中。导致这种潜在的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治疗药物来治疗血管钙化（即，动脉硬化）在细胞和分子水平上。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。这一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家庭的学生参与研究。该项目将通过研究以下假设来推进知识：VSMC持续可塑性为第三表型是由机械应变激活经典Wnt信号通路引起的。将使用体外血管钙化模型来检查机械转导在VSMC表型变化中的作用。该项目将：1）研究合成的VSMC中Wnt信号传导途径的激活; 2）检查表面力学对经由Wnt信号传导途径的表型调节的激活的影响;和3）检查VSMC在机械应变下的表型调节。 这种机械负荷将模拟VSMC对由于高血压而增加的拉伸的生理暴露，然后假设其引起组织内的响应以通过钙化增加其刚度并将应变范围恢复到组织特异性稳态水平。 该奖项反映了NSF的法定使命，并已被认为值得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的支持。