Chemical Tools to Study the Role of Biological Aldehydes

项目摘要/母公司赠款摘要： 低分子量醛(如甲醛和乙醛)的异常生产 脂肪衍生的醛(如4-羟基壬烯醛)对茎的老化有重要影响。 细胞。由醛介导的表观遗传修饰引起的分子水平的变化， DNA氧化损伤和DNA交联会导致多种人类疾病，包括 自身免疫性疾病、癌症、糖尿病和神经疾病。然而，我们的将军 由于缺乏方法，对机械基础的了解还不够 非侵入性地检测活性醛，操纵其亚细胞浓度，以及 以监测乙醛加工酶的活性。本申请中描述的项目 旨在通过开发新的化学物质来解决这三个研究领域中的每一个 工具。具体地说，我们将利用我们在分子成像和探测器方面的成熟专业知识 设计开发荧光和光声探测器，以非侵入性方式显示内源性 分别在细胞和整个动物水平上的醛。我们将补充这项工作 通过开发可用于输送特定醛物种的新的醛供体 按需使用灯光。由于光可以高精度地聚焦到小体积上 在一个细胞中，给定的反应醛的输送可以实现前所未有的 时空控制。最后，我们将开发新的荧光基质来监测 醛加工酶的酶活性在调节中起着至关重要的作用 干细胞的可塑性。这项工作将基于我们小组的最新研究，我们有 成功开发了一种通过升醛脱氢酶检测干细胞的新探针 1A1活性。在这项拟议的研究中，跨化学合成的综合方法 分子成像为研究反应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。

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.