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: 2129088
• 负责人: Siddharth Prakash
• 金额: $ 33.02万
• 依托单位: The University of Texas Health Science Center at Houston
• 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=2129088&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。这项工作将导致新的治疗方法，以改善全国健康。要研究疾病对女性和男性的不同影响，一种方法是将特纳综合症患者包括在内。和男性一样，特纳综合征患者只有一条X染色体，但他们出生时就有女性特征。这项研究的目标是识别调控心脏瓣膜细胞对力做出反应的X染色体基因。这种力量反应会影响二尖瓣的发育，并可能造成出生缺陷。这一问题在男性中比在女性中更常见，但在特纳综合征患者中的发病率是女性的50倍。患有二尖瓣和特纳综合征的人通常需要在相对较小的年龄进行主动脉瓣置换。不幸的是，即使通过成像也很难发现二尖瓣病变。这项研究将为需要外科瓣膜置换术的患者带来新的治疗方法。范围广泛的心血管疾病患者将从这些结果中受益，而不仅仅是特纳综合征患者。这个项目将涉及生物医学工程师、遗传学家和心脏病专家之间的合作。研究小组将对特纳综合症社区进行生物工程和研究方面的教育。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参与研究的范围。它还将促进发现和理解，同时促进教学、培训和学习。X染色体剂量是内皮向间充质转化的一种新的调节因素。了解细胞机械生物学的这一新方面将与性二态发育和疾病广泛相关。本研究将探讨血管内皮细胞向间充质转化的调节如何参与成人二尖瓣发育和二尖瓣纤维钙化改变。利用特纳综合征患者的细胞，研究小组将通过控制微环境、外部机械刺激和患者特定的特征来量化X染色体剂量在这种转化的机械调节中的作用。最后，将使用可诱导的转基因方法来纠正X染色体基因的表达，并逆转转化缺陷。这些数据将提供关于X染色体基因及其机械生物学在二尖瓣主动脉瓣中的作用的变革性新信息，并确定影响数百万患者的相关疾病的新治疗目标。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。