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: 10351102
• 负责人: Jody Ye
• 金额: $ 15.49万
• 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/10351102
• 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 physiology; Cells; Cellular Stress; Child; Clinical; DNA; 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-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 Analysis; Pathway interactions; Peptide Hydrolases; Play; Population; Prevalence; Research; Role; Running; Scientist; Stimulus; Structure of beta Cell of islet; System; Talents; Technology; Time; Training; Transgenic Mice; Translational Research; Translations; Viral; Virus Diseases; Work; autoimmune pathogenesis; base; biological adaptation to stress; career; college; early onset; education research; effective therapy; endoplasmic reticulum stress; epidemiology study; 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 这一K01奖项将允许易(Jody)Ye-Miller博士在以下领域推进她的独立研究生涯 1型糖尿病(T1D)。叶博士的首要职业目标是了解其致病机制 胰岛β细胞在T1D中的遗传和环境影响及其靶向途径 改善胰岛β细胞功能。拟议的项目是根据叶博士之前的工作和 培训她使用新的模型以及尖端技术来研究T1D的机制。 这是一个及时的机会和极好的培训工具，使一位才华横溢的年轻科学家能够 实现她的事业独立。阿尔伯特·爱因斯坦医学院是全国医学领域的领先者 教育、研究和医疗保健。该机构和叶博士的导师将提供支持 拥有所有必要设备和设施的环境，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，特别是在年轻人中 孩子们。目前的治疗方法不能提供改善β细胞功能的长期效果。病因学 T1D既有遗传因素也有环境因素，但我们对其潜在机制的理解 是不完整的，阻碍了新疗法的发展。在叶博士之前的博士后培训中，她 确定了两个T1D基因座，CTSH和PGM1，显示了遗传和环境影响的证据。 CTSH和PGM1在胰腺β细胞中均有表达。她的观察导致了这样一种假设 遗传和/或环境因素影响CTSH和PGM1的转录和翻译， 改变β细胞的功能和应激反应，从而触发T1D。 在这个项目中，叶博士将使用CRISPR-Cas9技术来修饰CTSH和PGM1在 人类胚胎干细胞。编辑后的干细胞随后将在 体外培养。叶博士将研究CTSH和PGM1在有和没有AN的情况下对β细胞功能的影响 环境刺激，如病毒感染。此外，叶博士将使用转基因小鼠模型来 研究CTSH或其相关途径是否可以靶向预防或延缓自身免疫性糖尿病 发展。 CTSH和PGM1是T1D相关基因，但其对β细胞的特异性作用尚不完全清楚 学习。提出的实验具有创新性和原创性。短期内，资金将使叶博士能够 在T1D领域确立了她的职业独立性。从长远来看，这些研究将揭开致病机理 CTSH和PGM1基因座相关的机制，允许开发新的治疗T1D的方法 人类。