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.

项目总结/摘要 这个K 01奖项将使Yi（Jody）Ye-Miller博士能够在以下领域推进她的独立研究生涯： 1型糖尿病（T1 D）。叶博士的首要职业目标是了解背后的致病机制， T1 D中胰腺β细胞的遗传和环境影响，并确定靶向途径， 改善β细胞功能。这个项目是在叶博士以前的工作基础上精心构思的， 训练她使用新颖的模型以及尖端技术来研究T1 D的潜在机制。 这是一个及时的机会和良好的培训工具，使一个非常有才华的年轻科学家， 实现职业独立。阿尔伯特·爱因斯坦医学院是医学领域的国家领导者。 教育、研究和医疗保健。该机构和叶博士的导师将提供支持 环境与所有必要的设备和设施，以及许多学习机会， 指导她的专业发展。 T1 D影响5%的美国人口，近几十年来患病率不断增加，尤其是在年轻人中 孩子目前的疗法无法提供长期的效果来改善β细胞功能。病因 T1 D的遗传和环境因素，但我们对潜在机制的理解 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， 鉴定了两个T1 D位点，CTSH和PGM 1，这表明遗传和环境影响的证据。 CTSH和PGM 1均在胰腺β细胞中表达。她的观察导致了这样的假设， 遗传和/或环境因素影响CTSH和PGM 1的转录和翻译， 改变β细胞的功能和应激反应，从而触发T1 D。 在这个项目中，叶博士将使用CRISPR-Cas9技术来修饰CTSH和PGM 1的表达， 人类胚胎干细胞经编辑的干细胞随后将分化为胰腺β细胞， 体外Ye博士将研究CTSH和PGM 1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， 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PGM 1是T1 D相关基因，但其对β细胞的特异性作用尚未彻底研究 研究了所提出的实验具有创新性和独创性。在短期内，资金将使叶博士 在T1 D领域建立职业独立性。从长远来看，这些研究将揭示致病性 与CTSH和PGM 1基因座相关的机制，允许开发新的疗法来治疗T1 D， 人类