Chemical Tools to Study the Role of Biological Aldehydes

研究生物醛作用的化学工具

• 批准号: 10474695
• 负责人: Jefferson Chan
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474695
• 关键词: 4 hydroxynonenal; Acetaldehyde; Address; Aging; Aldehydes; Animals; Area; Autoimmune Diseases; Biological; Biology; Cells; Chemicals; Complement; DNA; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Enzymes; Epigenetic Process; Formaldehyde; Health; Lead; Light; Lipids; Malignant Neoplasms; Mediating; Methods; Modification; Molecular; Molecular Weight; Monitor; Play; Population; Production; Regenerative capacity; Research; Role; Tissues; Work; aldehyde dehydrogenases; base; chemical synthesis; crosslink; design; healthy aging; human disease; imaging probe; insight; molecular imaging; nervous system disorder; oxidative DNA damage; spatiotemporal; stem cell aging; stem cell function; stem cells; tool

Project Summary/Abstract: Jefferson Chan, Ph.D. The aberrant production of low molecular weight aldehydes (i.e., formaldehyde and acetaldehyde) and lipid-derived aldehydes (e.g., 4-hydroxynonenal) have a major influence on the aging of stem cells. Molecular level changes that result from aldehyde-mediated epigenetic modifications, oxidative DNA damage and DNA cross-linking can lead to a variety of human diseases including autoimmune diseases, cancer, diabetes, and neurological disorders. However, our general understanding of the mechanistic underpinnings is insufficient owing to a dearth of methods to non-invasively detect reactive aldehydes, manipulate their subcellular concentrations, as well as to monitor the activity of aldehyde processing enzymes. The projects described in this application aim to address each of these three areas of research through the development of new chemical tools. Specifically, we will draw from our established expertise in molecular imaging and probe design to develop fluorescent and photoacoustic probes to non-invasively visualize endogenous aldehydes at the cellular and whole animal levels, respectively. We will complement this work by developing new aldehyde donors that can be employed to deliver a specific aldehyde species on demand using light. Since light can be focused with high precision onto small volumes within a cell, the delivery of a given reactive aldehyde can be achieved with unprecedented spatiotemporal control. Lastly, we will develop new fluorescent substrates to monitor the enzymatic activity of aldehyde processing enzymes implicated to play a crucial role in mediating stem cell plasticity. This work will be based on recent studies from our group where we have successfully developed a new probe to detect stem cells via elevated aldehyde dehydrogenase 1A1 activity. The integrated approach in this proposed research spanning chemical synthesis to molecular imaging offers an exciting opportunity to study the biology of reactive aldehyde species related to aging and associated disease states.

项目摘要/摘要：Jefferson Chan，Ph.D。 低分子量醛的异常产生（即甲醛和乙醛） 和脂质衍生的醛（例如，4-羟基苯烷）对茎的衰老有重大影响 细胞。醛介导的表观遗传修饰导致的分子水平变化， 氧化DNA损伤和DNA交联可能导致多种人类疾病 自身免疫性疾病，癌症，糖尿病和神经系统疾病。但是，我们的将军 由于缺乏方法，对机械基础的理解是不够的 非侵入性检测反应性醛，操纵其亚细胞浓度，以及 监测醛加工酶的活性。此应用程序中描述的项目 旨在通过开发新化学物质来解决这三个研究领域 工具。具体而言，我们将从我们既定的分子成像和探针方面的专业知识中获取 设计以开发荧光和光声探针以非侵入性可视化内源性 分别在细胞和整个动物水平的醛。我们将通过 开发新的醛供体，可用于在 使用光。由于光可以以高精度聚焦到一个小体积上 细胞，可以使用前所未有的时空来实现给定的反应性醛 控制。最后，我们将开发新的荧光基材，以监视 醛加工酶与介导干细胞可塑性中起着至关重要的作用。 这项工作将基于我们小组的最新研究，我们已经成功地开发了 通过升高的醛脱氢酶1a1活性检测干细胞的新探针。这 在这项拟议的研究中，综合方法涵盖化学合成至分子成像 提供了一个令人兴奋的机会来研究与衰老有关的反应性醛种的生物学 和相关疾病状态。