Investigating the functional roles of CTSH and PGM1 in beta-cells during autoimmune diabetes development

研究 CTSH 和 PGM1 在自身免疫性糖尿病发展过程中在 β 细胞中的功能作用

• 批准号: 10559637
• 负责人: Jody Ye
• 金额: $ 15.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559637
• 关键词: Affect; American; Antigen Presentation; Apoptosis; Area; Autoimmune; Autoimmune Diabetes; Autoimmune Responses; Automobile Driving; Beta Cell; CRISPR/Cas technology; CTSH gene; Cathepsins; Cell Death; Cell physiology; Cellular Stress; Child; Clinical; DNA Methylation; Data Analyses; Development; Diabetes Mellitus; Double-Stranded RNA; Environment; Environmental Risk Factor; Enzymes; Equipment; Etiology; Funding; Genes; Genetic; Genetic Risk; Genetic Transcription; Goals; Grant; Healthcare; Human; Hybrids; In Vitro; Inbred NOD Mice; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Knock-out; Knowledge; Learning; LoxP-flanked allele; Lysosomes; Mediating; Medical Education; Medicine; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mus; Pathogenicity; Pathway interactions; Peptide Hydrolases; Play; Population; Prevalence; Research; Role; Running; Scientist; Stimulus; Structure of beta Cell of islet; System; Talents; Technology; Training; Transgenic Mice; Translational Research; Translations; Viral; Virus Diseases; Work; autoimmune pathogenesis; biological adaptation to stress; career; college; early onset; effective therapy; endoplasmic reticulum stress; experimental study; gene product; genetic epidemiology; genetic risk factor; genome wide association study; glycogenesis; glycogenolysis; glycosylation; human embryonic stem cell; immunogenicity; improved; in vitro Model; innovation; interest; islet; mouse model; novel; novel therapeutics; overexpression; post-doctoral training; preservation; prevent; protein degradation; response; risk variant; stem cell differentiation; stem cells; supportive environment

Project Summary / Abstract This K01 award will allow Dr. Yi (Jody) Ye-Miller to advance her independent research career in the field of type 1 diabetes (T1D). Dr. Ye’s overarching career goal is to understand the pathogenic mechanisms behind the genetic and environmental influence of pancreatic beta-cells in T1D and to identify targeted pathways to improve beta-cell function. The proposed project is carefully conceived, based on Dr.Ye’s previous work and trains her to use novel models as well as cutting-edge technologies to study the mechanisms underlying T1D. It is a timely opportunity and excellent training vehicle to enable an extremely talented young scientist to achieve her career independence. The Albert Einstein College of Medicine is a national leader in medical education, research, and health care. The institution and Dr. Ye’s mentors will provide a supportive environment with all the necessary equipment and facilities, as well as many learning opportunities and guidance for her professional development. T1D affects 5% of the U.S. population with increasing prevalence in recent decades, especially among young children. Current therapies are unable to provide long-lasting effects to improve beta cell function. The etiology of T1D has both genetic and environmental components, but our understanding of the underlying mechanisms is incomplete, hindering the development of novel therapies. In Dr. Ye’s previous postdoctoral trainings, she identified two T1D loci, CTSH and PGM1, which showed evidence of genetic and environmental influence. Both CTSH and PGM1 are expressed in pancreatic beta-cells. Her observations led to the hypothesis that genetic and/or environment factors influence CTSH and PGM1 transcription and translation, which alter the function and stress-response of beta-cells that consequently trigger T1D. In this project, Dr. Ye will use CRISPR-Cas9 technology to modify the expression of CTSH and PGM1 in human embryonic stem cells. Edited stem cells will subsequently be differentiated into pancreatic beta-cells in vitro. Dr. Ye will investigate the effect of CTSH and PGM1 on beta-cell function with and without an environmental stimulus such as viral infection. In addition, Dr. Ye will use a transgenic mouse model to investigate whether CTSH or its related pathways can be targeted to prevent or slow autoimmune diabetes development. CTSH and PGM1 are T1D associated genes, but their beta-cells specific effects have not been thoroughly studied. The proposed experiments are innovative and original. In a short term, funding will allow Dr. Ye to establish her career independence in the field of T1D. In a long run, these studies will unravel the pathogenic mechanisms associated with CTSH and PGM1 loci, allowing the development of new therapies to treat T1D in humans.

项目摘要 /摘要 该K01奖将使Yi（Jody）Ye-Miller博士能够在她在该领域的独立研究生涯中发展 1型糖尿病（T1D）。叶博士的总体职业目标是了解背后的病原机制 胰腺β细胞在T1D中的遗传和环境影响，并确定有针对性的途径 提高β细胞功能。根据Ye博士以前的工作，对拟议的项目进行了精心构想。 训练她使用新型模型以及尖端的技术来研究T1D的基础机制。 这是一个及时的机会和出色的训练工具，使一位非常有才华的年轻科学家能够 实现她的职业独立性。阿尔伯特·爱因斯坦医学院是医学的国家领导者 教育，研究和医疗保健。该机构和叶博士的导师将提供支持 具有所有必要设备和设施的环境，以及许多学习机会和 她的专业发展指导。 近几十年来，T1D影响了5％的美国人口，尤其是在年轻人中的患病率的增加 孩子们。当前的疗法无法提供长期效果以改善β细胞功能。病因 T1D的遗传和环境成分既有遗传成分，但是我们对基本机制的理解 是不完整的，阻碍了新型疗法的发展。在叶博士以前的博士后培训中，她 确定了两个T1D基因座，CTSH和PGM1，这表明了遗传和环境影响的证据。 CTSH和PGM1均在胰腺β细胞中表达。她的观察导致了以下假设 遗传和/或环境因素影响CTSH和PGM1转录和翻译，这 改变因此触发T1D的β细胞的功能和应力反应。 在这个项目中，Ye博士将使用CRISPR-CAS9技术来修改CTSH和PGM1的表达 人类胚胎干细胞。随后，编辑的干细胞将分为胰腺β细胞 体外。 Ye博士将研究CTSH和PGM1对有和不带有beta-cell功能的影响 环境刺激，例如病毒感染。此外，Ye博士将使用转基因小鼠模型 调查CTSH及其相关途径是否可以针对预防或减慢自身免疫性糖尿病 发展。 CTSH和PGM1是T1D相关的基因，但是它们的β细胞特异性尚未彻底 Studiod。提出的实验是创新的和原始的。在短期内，资金将允许Ye博士 在T1D领域建立自己的职业独立性。从长远来看，这些研究将揭示病原体 与CTSH和PGM1基因座相关的机制，允许开发新疗法来治疗T1D 人类。