Chemical Tools to Study the Role of Biological Aldehydes

项目摘要/摘要：Jefferson Chan博士 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。我们将通过以下方式补充这项工作 开发新的醛供体，可用于在 用光需求。由于光可以高精度地聚焦到一个 细胞中，给定的反应醛的传递可以以前所未有的时空实现 控制力。最后，我们将开发新的荧光底物来监测酶的活性 醛加工酶在调节干细胞可塑性方面起着至关重要的作用。 这项工作将基于我们小组最近的研究，我们已经成功地开发了 一种通过提高乙醛脱氢酶1A1活性检测干细胞的新探针。这个 从化学合成到分子成像的这项拟议研究的综合方法 提供了一个令人兴奋的机会来研究与衰老有关的反应醛物种的生物学 以及相关的疾病状态。

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.