Chemical Tools to Study the Role of Biological Aldehydes

研究生物醛作用的化学工具

• 批准号: 10157865
• 负责人: Jefferson Chan
• 金额: $ 5.53万
• 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/10157865
• 关键词: 4 hydroxynonenal; Acetaldehyde; Acids; Acoustics; Active Sites; Address; Aging; Aldehydes; Animals; Area; Autoimmune Diseases; Back; Biological; Biology; Brain; Cell Culture Techniques; Cell Differentiation process; Cell physiology; Cells; Chemicals; Complement; Coupled; Culture Media; Cysteine; DNA; Detection; Development; Diabetes Mellitus; Disease; Enzymes; Epigenetic Process; Family; Fluorescence; Fluorescent Probes; Formaldehyde; Goals; Health; Human; Image; Inflammation; Ions; Lead; Light; Lipids; Location; Malignant Neoplasms; Mediating; Metals; Methanol; Methods; Modification; Molecular; Molecular Weight; Monitor; Nitric Oxide; Oxygen; Phenotype; Play; Population; Production; Protein Isoforms; Research; Resolution; Retina; Role; Signal Pathway; Signal Transduction; Supplementation; Techniques; Temperature; Three-Dimensional Image; Tissues; Transducers; Tretinoin; Ultrasonography; Visible Radiation; Vitamin A; Work; Xenobiotics; aldehyde dehydrogenases; analog; base; cancer stem cell; chemical synthesis; crosslink; design; feeding; fluorescence imaging; healthy aging; human disease; imaging agent; imaging probe; in vivo; insight; interest; molecular imaging; nervous system disorder; oxidation; oxidative DNA damage; parent grant; photoacoustic imaging; pressure; regenerative; self-renewal; small molecule; spatiotemporal; stem cells; stem-like cell; stemness; tool; tumor; unnatural amino acids

Project Summary/Abstract of Parent Grant: 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 successfullydeveloped 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.

项目概要/家长资助摘要： 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-羟基壬烯醛）对茎的老化有重要影响 细胞由甜菜碱介导的表观遗传修饰引起的分子水平变化， 氧化性DNA损伤和DNA交联可导致多种人类疾病， 自身免疫性疾病、癌症、糖尿病和神经系统疾病。然而，我们的将军 由于缺乏方法， 非侵入性检测活性醛，操纵其亚细胞浓度，以及 以监测醛加工酶的活性。本申请书所述的项目 旨在通过开发新的化学品来解决这三个研究领域中的每一个 工具.具体来说，我们将利用我们在分子成像和探针方面的专业知识， 设计开发荧光和光声探针，以非侵入性地可视化内源性 醛在细胞和整个动物水平，分别。我们将补充这项工作 通过开发新的醛供体， 按需使用光。由于光可以高精度地聚焦到内部的小体积上， 在细胞中，给定的反应性醛的递送可以以前所未有的 时空控制最后，我们将开发新的荧光底物来监测 醛加工酶的酶活性暗示在介导 干细胞可塑性这项工作将基于我们小组最近的研究， 成功开发了一种通过乙醛脱氢酶升高检测干细胞的新探针 1A 1活动在这项拟议的研究中，综合方法涵盖化学合成， 分子成像为研究活性醛的生物学提供了一个令人兴奋的机会 与衰老和相关疾病状态有关的物种。