Impact of a Novel Secreted Enzyme J18 on Healthspan and Lifespan

项目摘要/摘要 这份提案概述了赵善刚博士要完成的综合培训和研究计划 在Philipp E.Scherer博士的指导下进行进一步的学术培训，并过渡到 专门从事新陈代谢和老年科学领域的独立研究人员。总体目标 这项研究提案的目的是探索一种新的分泌蛋白，即J18在 健康寿命和寿命。在小鼠和人的唾液腺中高表达，大量 糖基化的J18被分泌到唾液中，这是一种容易获得的多种生物医学材料 化验。J18表现出一种独特的调节模式：其水平在新陈代谢健康的状态下增加， 如禁食和卡路里限制，而在代谢不利条件下减少，如 衰老和肥胖。根据我们的J18转基因和基因敲除小鼠模型积累的证据， 我们发现J18是一种新的脂水解酶，它针对一种独特的脂类来调节其效力 促进新陈代谢健康的作用。此外，初步数据表明，增加J18水平在 我们的肝脏J18转基因小鼠似乎延长了J18全球KO中J18的寿命和缺陷 老鼠会缩短中位寿命。J18生理学的基本原理被显著地保守了 从老鼠到人类。这些发现帮助我们定义了以前的 代谢方面的未知蛋白J18。我们将利用我们新产生的组织特异性 转基因和KO小鼠模型，以操纵系统J18水平，以及J18靶向独特 脂类，并将致力于：1)唾液来源的J18可能是一个潜在的和新的老化生物标志物 允许轻松预测个人的预期寿命；2)J18对健康寿命和寿命的影响。 总而言之，这些研究将为J18在体内的生理作用提供重要的新见解。 健康寿命和寿命。J18作为潜在的衰老生物标志物的拟议角色满足了迫切的需求 需要一种易于分析、验证和有效的衰老生物标志物，并将极大地促进 老年科学方面的研究。在德克萨斯大学西南医学中心的赞助下， 连同之前在研究脂联素对健康寿命的影响方面获得的经验，我将 由国际公认的新陈代谢领域的领导者指导，并由顶尖的衰老专家提供建议， 这将极大地促进我的研究生涯向独立调查员的过渡 位置。

Project Summary/Abstract This proposal outlines an integrated training and research plan for Dr. Shangang Zhao to complete further academic training under the mentorship of Dr. Philipp E. Scherer and transition to an independent investigator specializing in the field of metabolism and geroscience. The overall objective of the research proposal is to explore the impact of a novel secreting protein, referred to as “J18” in healthspan and lifespan. Highly expressed in salivary glands both in mouse and human, large amounts of glycosylated J18 are secreted into saliva, an easily accessible biomaterial for multiple biomedical assays. J18 displays a unique pattern of regulation: Its level is increased in metabolically healthy states, such as fasting and calorie restriction, while decreased in metabolically adverse conditions, such as aging and obesity. With evidence accumulated from our J18 transgenic and knockout mouse models, we found that J18 is a novel lipid hydrolase, targeting on a unique lipid class to mediate its potent effects in promoting metabolic health. In addition, preliminary data suggest that increasing J18 level in our liver J18 transgenic mouse seems to prolong life span and deficiency of J18 in our J18 global KO mice reduces median life span. The basic principle of J18 physiology has been conserved remarkably well from mouse to human. These findings helped us define the physiological role of a previously unknown protein J18 in metabolic aspect. We will take advantage of our newly generated tissue specific transgenic and KO mouse models to manipulate systemic J18 level, along with the J18 targeted- unique lipid class, and will address: 1) saliva-derived J18 may be a potential and novel aging biomarker to allow easy prediction of an individual's life expectancy; 2) the impact of J18 in healthspan and lifespan. Combined, these studies will provide significant new insights into the physiological effects of J18 in healthspan and lifespan. The proposed role of J18 as a potential aging biomarker meets the urgent need for an easily assayable, validated and effective aging biomarker, and will greatly advance research in geroscience. Under the auspices of the University of Texas Southwestern Medical Center, along with the previous experience gained in studying the impact of adiponectin in healthspan, I will be mentored by internationally recognized leaders in the metabolism, and advised by the top aging experts, which will greatly facilitate the transition of my research career toward an independent investigator position.