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.

项目摘要/摘要该建议概述了Shangang Zhao博士完成的综合培训和研究计划在Philipp E. Scherer博士的心态下进行进一步的学术培训，并过渡到独立研究者专门研究代谢和Geroscience领域。总体目标研究建议的是探索一种新型分泌蛋白的影响，称为“ J18” HealthSpan和寿命。在小鼠和人类的唾液烤架中高度表达，大量糖基化的J18的分泌成唾液，这是一种易于获得的生物材料的生物材料测定。 J18显示了一种独特的调节模式：在代谢健康状态下，其水平有所提高，例如禁食和卡路里限制，同时在代谢广告条件下逐渐下降，例如衰老和肥胖。从我们的J18转基因和敲除小鼠模型中积累的证据，我们发现J18是一种新型的脂质水解酶，靶向独特的脂质类，以介导其有效性促进代谢健康的影响。此外，初步数据表明J18水平增加我们的肝J18转基因老鼠似乎延长了J18 Global KO中J18的寿命和缺乏小鼠减少了中位寿命。 J18生理学的基本原理已得到明显保存从老鼠到人。这些发现帮助我们定义了以前的身体角色代谢方面未知蛋白J18。我们将利用新生成的组织特定的优势转基因和KO鼠标模型操纵系统性J18级别，以及J18靶向独特的脂质类，并将解决：1）唾液来源的J18可能是一种潜在的新型衰老生物标志物轻松预测个人的预期寿命； 2）J18在HealthSpan和寿命中的影响。这些研究结合在一起，将为J18的物理影响提供重大的新见解 HealthSpan和寿命。 J18作为潜在衰老生物标志物的拟议角色符合紧急需要易于测定，经过验证且有效的老化生物标志物，并将大大进步 Geroscience的研究。在德克萨斯大学西南医学中心的主持下，除了研究脂联素对HealthSpan的影响方面所获得的先前经验，我将由国际公认的新陈代谢领导者指导，并在老龄化专家的建议下，这将极大地支持我的研究生涯向独立研究者的过渡位置。