Chemical Tools to Study the Role of Biological Aldehydes

研究生物醛作用的化学工具

基本信息

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
项目类别：
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

项目摘要

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.

父母赠款的项目摘要/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。我们将补充这项工作通过开发可用于提供特定醛的新醛供体按需使用光。由于光可以以高精度聚焦到内部的小体积上一个细胞，可以在前所未有的情况下实现给定的反应性醛时空对照。最后，我们将开发新的荧光基质以监视醛加工酶的酶促活性与介导有关起着至关重要的作用干细胞塑性。这项工作将基于我们小组的最新研究成功地开发了一种新的探针，通过升高的醛脱氢酶检测干细胞 1A1活动。这项拟议研究的综合方法涵盖化学合成至分子成像为研究反应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。