Collaborative Research: The Role of Force, Flow, and Female Sex in Heart Development: Bicuspid Aortic Valve in Turner Syndrome

合作研究：力、流量和女性性别在心脏发育中的作用：二叶式主动脉瓣在特纳综合征中的作用

• 批准号: 2129122
• 负责人: Kathryn Grande-Allen
• 金额: $ 31.2万
• 依托单位: William Marsh Rice University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2129122&HistoricalAwards=false
• 关键词: Collaborative; Research; Role; Force; Flow

This research will study how blood flow affects diseases of the heart and blood vessels differently in men and women. The work will lead to new treatments to improve nationwide health. One way to study how diseases affect women and men differently is to include people with Turner Syndrome. Like men, people with Turner Syndrome have only one X chromosome, but they are born with female features. The goal of this research is to identify X chromosome genes that regulate how heart valve cells respond to forces. This force response affects the development of the bicuspid aortic valve, and can create a birth defect. This problem is more common in men than in women, but is 50 times more common in people with Turner Syndrome. People with a bicuspid aortic valve and Turner Syndrome often need to have their aortic valves replaced at a relatively young age. Unfortunately, it is very hard to detect bicuspid aortic valve disease, even with imaging. This research will lead to new treatments for patients who need surgical valve replacement. A broad range of cardiovascular disease patients will benefit from these results, not only those with Turner Syndrome. This project will involve a collaboration between biomedical engineers, geneticists, and cardiologists. The research team will educate the Turner Syndrome community about bioengineering and the research. By training graduate, undergraduate, and high school students, this project will broaden participation of underrepresented groups in research. It will also advance discovery and understanding while promoting teaching, training, and learning.X chromosome dosage is a novel regulatory factor for endothelial to mesenchymal transformation. Understanding this novel aspect of cell mechanobiology will be broadly relevant to sexually dimorphic development and disease. This research will address how regulation of endothelial to mesenchymal transformation is involved in bicuspid aortic valve development and fibrocalcific changes of bicuspid valves in adults. Using cells from Turner Syndrome patients, the research team will quantify a role for X chromosome dosage in mechanical regulation of this transformation by controlling the microenvironment, exogenous mechanical stimuli, and patient-specific characteristics. Finally, inducible transgenic approaches will be used to correct X chromosome gene expression and reverse the transformation defects. This data will provide transformational new information on the role of X chromosome genes and their mechanobiology in bicuspid aortic valves and identify new therapeutic targets for related diseases that affect millions of patients.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.

这项研究将研究血液流动对男性和女性心脏和血管疾病的不同影响。这项工作将带来新的治疗方法，以改善全国的健康状况。研究疾病对女性和男性的影响有何不同的一种方法是将特纳综合症患者纳入研究对象。与男性一样，特纳综合症患者只有一条X染色体，但他们天生具有女性特征。这项研究的目的是确定调节心脏瓣膜细胞如何对外力作出反应的X染色体基因。这种力反应会影响二尖瓣主动脉瓣的发育，并可能造成出生缺陷。这个问题在男性中比在女性中更常见，但在特纳综合症患者中患病率是女性的50倍。患有二尖瓣主动脉瓣和特纳综合征的人通常需要在相对年轻的时候更换主动脉瓣。不幸的是，即使有影像学检查，也很难发现二尖瓣主动脉瓣疾病。这项研究将为需要手术瓣膜置换术的患者带来新的治疗方法。广泛的心血管疾病患者将受益于这些结果，而不仅仅是那些患有特纳综合征的患者。这个项目将涉及生物医学工程师、遗传学家和心脏病学家之间的合作。研究小组将教育特纳综合症社区有关生物工程和研究。通过培训研究生、本科生和高中生，该项目将扩大未被充分代表的群体在研究中的参与。它还将促进发现和理解，同时促进教学、培训和学习。X染色体剂量是内皮细胞向间充质细胞转化的一个新的调控因子。理解细胞力学生物学的这一新方面将与两性二态发育和疾病广泛相关。本研究将探讨内皮细胞向间充质细胞转化的调节如何参与成人二尖瓣主动脉瓣发育和二尖瓣纤维钙化变化。利用来自特纳综合征患者的细胞，研究小组将通过控制微环境、外源性机械刺激和患者特异性特征，量化X染色体剂量在这种转化的机械调节中的作用。最后，利用诱导型转基因方法纠正X染色体基因表达，逆转转化缺陷。这些数据将为X染色体基因及其在二尖瓣主动脉瓣中的作用提供革命性的新信息，并为影响数百万患者的相关疾病确定新的治疗靶点。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。