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.

项目概要/摘要 该 K01 奖项将使 Yi (Jody) Ye-Miller 博士能够推进她在该领域的独立研究生涯 叶博士的首要职业目标是了解 1 型糖尿病 (T1D) 背后的致病机制。 胰腺 β 细胞对 T1D 的遗传和环境影响，并确定靶向途径 改善β细胞功能的提议项目是在叶博士之前的工作和基础上精心构思的。 训练她使用新颖的模型和尖端技术来研究 T1D 的机制。 这是一个及时的机会和极好的培训工具，使一位非常有才华的年轻科学家能够 阿尔伯特·爱因斯坦医学院是全国医学领域的领先者。 该机构和叶博士的导师将提供支持。 拥有所有必要的设备和设施的环境，以及许多学习机会和 为她的职业发展提供指导。 T1D 影响着 5% 的美国人口，近几十年来患病率不断上升，尤其是在年轻人中 目前的疗法无法提供改善β细胞功能的持久效果。 T1D 的发病既有遗传因素，也有环境因素，但我们对潜在机制的了解 不完整，阻碍了叶博士之前的博士后培训。 确定了两个 T1D 基因座 CTSH 和 PGM1，这显示了遗传和环境影响的证据。 CTSH 和 PGM1 均在胰腺 β 细胞中表达。她的观察得出了这样的假设： 遗传和/或环境因素影响 CTSH 和 PGM1 转录和翻译，其中 改变 β 细胞的功能和应激反应，从而引发 T1D。 在这个项目中，叶博士将利用CRISPR-Cas9技术来修饰CTSH和PGM1的表达 人类胚胎干细胞随后将分化为胰腺β细胞。 叶博士将在体外研究 CTSH 和 PGM1 对 β 细胞功能的影响。 此外，叶博士还将使用转基因小鼠模型来研究病毒感染等环境刺激。 研究 CTSH 或其相关通路是否可以预防或减缓自身免疫性糖尿病 发展。 CTSH和PGM1是T1D相关基因，但它们对β细胞的特异性作用尚未得到彻底研究 所提出的实验具有创新性和原创性，在短期内，资金将使叶博士能够实现这一目标。 从长远来看，这些研究将揭示她在 T1D 领域的职业独立性。 与 CTSH 和 PGM1 基因座相关的机制，允许开发治疗 T1D 的新疗法 人类。