Effects of Mechanically-Induced Stress on the Proteome and Development

机械应力对蛋白质组和发育的影响

• 批准号: 1946456
• 负责人: Philip LeDuc
• 金额: $ 47.52万
• 依托单位: Carnegie-Mellon University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1946456&HistoricalAwards=false
• 关键词: Effects; Mechanically; Induced; Stress; Proteome

This grant will support work to better understand how the physical environment influences biology. Specifically, this grant will support work to better understand how proteins respond to mechanical forces. Organisms are continuously sensing mechanical forces and respond appropriately. For example, the Earth’s gravity is constantly pulling down and the atmospheric pressure which compresses from all directions, yet organisms can remain upright. If the ability to sense these physical effects is compromised, it can lead to developmental disorders, muscle and bone loss, neurological abnormalities, immunological, and age-related problems. These conditions have been observed even in astronauts, who are exposed to microgravity during prolonged times away from Earth. The work done under this grant use novel microtechnology systems that mimic different physical environments. These microtechnology systems will be used to investigate how mechanical changes in the physical environment differentially affect thousands of proteins. Characterizing these biological responses will ultimately lead to improvements in national health. For example, the results of this work may ultimately inform future therapeutic strategies or disease prevention techniques. This project will also create an educational and training program for interdisciplinary collaboration. Engineers and biological scientists will work together, and participation in research for underrepresented groups will be broadened. Different types of Earth’s physical forces continuously impact living beings as a part of their ceaseless adaptation to external stimuli. While much is known about mechanotransduction in specific sensory systems, little is known about generalized mechanosensation of the surrounding physical environment by whole organisms. One reason for this lack of knowledge is the limited methods to mechanically stimulate enough whole organisms to enable comprehensive proteomic analysis. To investigate generalized mechanosensation, hundreds of living Drosophila embryos will be exposed to multiple modes, amplitudes, and durations of various mechanical stimulation such as microgravity, hypergravity, and external compression using microfabricated high-throughput devices that will be developed. This work will utilize the comparative proteomics approach of 2D-DIGE (2 Dimensional Difference Gel Electrophoresis) to identify changes in protein abundance or post-translational regulation in response to these different modes of mechanical stimulation. This approach will also enable the proteomic comparison of local/acute to chronic/ubiquitous mechanical stimulation. By using comparative proteomics in conjunction with the analysis of developmental phenotypes, the extent to which these mechanical modes are specialized, or overlap in a universal pathway of mechanotransduction in the context of whole organisms will be examined.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.

这笔赠款将支持更好地了解物理环境如何影响生物学的工作。具体地说，这笔赠款将支持更好地了解蛋白质如何响应机械力的工作。生物体不断地感知机械力，并做出适当的反应。例如，地球的重力不断向下拉，大气压力从各个方向压缩，但生物体可以保持直立。如果感知这些物理影响的能力受损，可能会导致发育障碍、肌肉和骨骼丢失、神经异常、免疫学和与年龄相关的问题。甚至在宇航员身上也观察到了这些情况，他们在远离地球的很长一段时间里暴露在微重力下。在这项拨款下完成的工作使用了模拟不同物理环境的新型微技术系统。这些微技术系统将被用来研究物理环境中的机械变化如何以不同的方式影响数千种蛋白质。确定这些生物反应的特征将最终导致国民健康的改善。例如，这项工作的结果可能最终会为未来的治疗策略或疾病预防技术提供参考。该项目还将创建一个跨学科协作的教育和培训计划。工程师和生物科学家将共同努力，并将扩大对代表性不足群体的研究参与。作为生物不断适应外界刺激的一部分，地球上不同类型的物理力量不断地影响着生物。虽然人们对特定感官系统中的机械转导知之甚少，但对整个生物体对周围物理环境的普遍机械感觉知之甚少。缺乏这种知识的一个原因是，机械刺激足够多的整个生物体以进行全面的蛋白质组学分析的方法有限。为了研究普遍的机械感觉，数百个活的果蝇胚胎将使用即将开发的微型制造高通量设备，暴露在各种机械刺激的多种模式、幅度和持续时间中，如微重力、超重力和外压缩。这项工作将利用2D-DGE(二维差异凝胶电泳法)的比较蛋白质组学方法来识别蛋白质丰度的变化或翻译后调节对这些不同的机械刺激模式的响应。这种方法还将使局部/急性和慢性/无处不在的机械刺激的蛋白质组学比较成为可能。通过将比较蛋白质组学与发育表型分析相结合，将检查这些机械模式的专门化程度，或在整个生物体范围内的机械转导的普遍途径中重叠的程度。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。

项目成果

3D Collagen Vascular Tumor-on-a-Chip Mimetics for Dynamic Combinatorial Drug Screening.

3D胶原蛋白血管肿瘤在片上，用于动态组合药物筛查。

• DOI: 10.1158/1535-7163.mct-20-0880
• 发表时间: 2021-06
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Wan L;Yin J;Skoko J;Schwartz R;Zhang M;LeDuc PR;Neumann CA
• 通讯作者: Neumann CA

Decidual Vasculopathy Identification in Whole Slide Images Using Multiresolution Hierarchical Convolutional Neural Networks

• DOI: 10.1016/j.ajpath.2020.06.014
• 发表时间: 2020-10-01
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Clymer, Daniel;Kostadinov, Stefan;LeDuc, Philip
• 通讯作者: LeDuc, Philip

3D In Vitro Neuron on a Chip for Probing Calcium Mechanostimulation

• DOI: 10.1002/adbi.202000080
• 发表时间: 2020-09-02
• 期刊: ADVANCED BIOSYSTEMS
• 影响因子: 4.1
• 作者: Bobo, Justin;Garg, Akash;LeDuc, Philip R.
• 通讯作者: LeDuc, Philip R.

Tracking of Scalpel Motions With an Inertial Measurement Unit System

• DOI: 10.1109/jsen.2022.3145312
• 发表时间: 2022-03-01
• 期刊: IEEE SENSORS JOURNAL
• 影响因子: 4.3
• 作者: Kabuye, Ernest;Hellebrekers, Tess;Leduc, Philip
• 通讯作者: Leduc, Philip

Inducing Vascular Grammars for Anomaly Classification in Brain Angiograms

诱导血管语法用于脑血管造影中的异常分类

• DOI: 10.1115/1.4053424
• 发表时间: 2022
• 期刊: Journal of Engineering and Science in Medical Diagnostics and Therapy
• 作者: Whiting, Mark E.;Mettenburg, Joseph;Novelli, Enrico M.;Santini, Tales;Martins, Tiago;Ibrahim, Tamer S.;LeDuc, Philip R.;Cagan, Jonathan
• 通讯作者: Cagan, Jonathan