Impact of a Novel Secreted Enzyme J18 on Healthspan and Lifespan

新型分泌酶 J18 对健康和寿命的影响

基本信息

批准号：
10468187
负责人：
Shangang Zhao
金额：
$ 11.32万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468187
关键词：
Academic Training Address Adipose tissue Affect Age Aging Antidiabetic Drugs Biocompatible Materials Biological Biological Assay Biological Markers Body Weight Caloric Restriction Cellular biology Data Diet Disease Eating Enzymes Family Fasting Functional disorder Gene Expression Genes Geroscience Goals Health High Fat Diet Human Hydrolase Impairment Individual Insulin Resistance International Knockout Mice Label Life Life Expectancy Link Lipids Liver Longevity Measures Mediating Medical center Mentors Mentorship Metabolic Metabolism Mus Obese Mice Obesity Pattern Persons Pharmacology Phase Phenotype Physiological Physiology Positioning Attribute Process Proteins Recombinants Regulation Research Research Personnel Research Proposals Rodent Role Saliva Salivary Glands Testing Texas Therapeutic Time Tissues Training Transgenic Mice Transgenic Organisms Universities adiponectin age related aged base behavior test career cognitive function cohort combat disorder risk experience feeding glucose tolerance healthspan high throughput screening impaired glucose tolerance improved in vivo insight insulin sensitivity interdisciplinary approach interest mouse model novel novel strategies overexpression potential biomarker predictive marker secretory protein tumor

项目摘要

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.

项目概要/摘要该提案概述了赵山刚博士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者。该研究计划的目的是探索一种新型分泌蛋白的影响，该蛋白在医学中被称为“J18” 在小鼠和人类的唾液腺中大量表达。糖基化 J18 分泌到唾液中，这是一种易于获取的生物材料，可用于多种生物医学 J18 显示出独特的调节模式：其水平在代谢健康状态下增加，例如禁食和热量限制，而在代谢不利条件下减少，例如根据我们的 J18 转基因和基因敲除小鼠模型积累的证据，我们发现 J18 是一种新型脂质水解酶，针对独特的脂质类别来介导其有效的此外，初步数据表明，提高 J18 水平可促进代谢健康。我们的肝脏J18转基因小鼠似乎可以延长寿命，而我们的J18全球KO中缺乏J18 小鼠的中位寿命缩短 J18 生理学的基本原理得到了保守的保护。从小鼠到人类，这些发现帮助我们定义了先前的生理作用。代谢方面的未知蛋白质 J18 我们将利用我们新生成的组织特异性。转基因和 KO 小鼠模型可操纵全身 J18 水平，以及 J18 靶向独特的脂质类，并将解决：1）唾液衍生的 J18 可能是一种潜在的新型衰老生物标志物可以轻松预测个人的预期寿命；2）J18 对健康寿命和寿命的影响。结合起来，这些研究将为 J18 在体内的生理效应提供重要的新见解。 J18 作为潜在衰老生物标志物的作用满足了迫切的需求。需要一种易于检测、验证和有效的衰老生物标志物，并将极大地推进在德克萨斯大学西南医学中心的赞助下进行老年科学研究。结合之前研究脂联素对健康寿命的影响所获得的经验，我将由国际公认的新陈代谢领域的领导者指导，并由顶级衰老专家提供建议，这将极大地促进我的研究生涯向独立研究者的转变位置。