Evaluation of the Effect of Autoimmunity on Acinar-Derived Insulin Producing Cells

自身免疫对腺泡源性胰岛素产生细胞影响的评价

• 批准号: 10185387
• 负责人: FARZAD ESNI
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-25 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10185387
• 关键词: Acinar Cell; Address; Adoptive Transfer; Adult; Alpha Cell; Amylases; Area; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Beta Cell; Blood Glucose; Cell Count; Cells; Cellular biology; Chemicals; Chronic; Clinical; Clinical Trials; Clone Cells; Diabetes Mellitus; Diabetic mouse; Disease; Eating; Endocrine; Ensure; Environment; Enzymes; Evaluation; Focal Adhesion Kinase 1; Food; Generations; Genes; Genetic; Glucose; Goals; Human; Immune; Immunocompetent; Immunogenetics; Immunosuppression; Immunotherapy; In Vitro; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Invaded; Islets of Langerhans Transplantation; Lead; Location; Malignant Neoplasms; Metabolic Diseases; Modeling; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Pancreas; Pharmacology; Phosphotransferases; Positioning Attribute; Preparation; Procedures; Publications; Reporting; Research; Research Personnel; Resistance; SCID Mice; Signal Transduction; Somatic Cell; Source; Splenocyte; Syndrome; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Viral; Work; adult stem cell; autoimmune pathogenesis; autoreactive T cell; beta cell replacement; cell replacement therapy; cell type; diabetogenic; embryonic stem cell; euglycemia; experimental study; immunogenicity; immunoregulation; in vivo; islet; pancreas development; prevent; single-cell RNA sequencing; transdifferentiation; transplantation therapy

Diabetes is a syndrome defined by high blood glucose levels caused by either reduction in number of insulin- producing cells (Type 1 diabetes), or the ability of our cells to respond to insulin in combination with declined numbers of insulin-producing cell number (Type 2 diabetes). Thus, a cure for diabetes should entail replacement of insulin-producing β-cells. There have been tremendous efforts throughout the years to generate β-cells from different sources, not only from embryonic stem cells, and adult stem or somatic cells, but also from non-β-cells residing in the pancreas. One such cell type is the amylase-producing pancreatic acinar cell. These cells are primarily responsible for producing and secreting enzymes that would help us digest of the food we eat. The acinar cells also represent the majority of cells in the pancreas, thus they are perfect as the source for new β-cell generation. Here, we provide evidence that both genetic as well as pharmacological inactivation of focal adhesion kinase (FAK) converts pancreatic acinar cells into insulin-producing cells in vivo. The acinar-derived insulin-producing (ADIP) cells invade the preexisting islets and are able to restore normoglycemia in non-autoimmune diabetic mice. In the current proposal, we will determine whether ADIP cells can survive, be functional and prevent diabetes in an autoimmune setting. The overall goal of this project is to determine the ability of ADIP cells to survive and avoid autoimmune attack. As a first step, we will study the effect of FAKi on T cells (aim 1). Next, we will determine whether ADIP cells can escape autoimmune T cell attack (aim 2). Finally, we will compare the expression profile of ADIP cells compared to regular β-cells (aim 3). This work is a high priority area as it is directly applicable to our full understanding and potential treatment of Type 1 and Type 2 diabetes, and may provide a key understanding of how to generate new functional β-cells from acinar cells. This procedure may result in reversal of diabetes without islet transplantation and immune suppression. More importantly, if successful, it should position us well in preparation for clinical trials in humans with diabetes.

糖尿病是一种由高血糖水平定义的综合征，原因是产生胰岛素细胞的数量减少（1型糖尿病），或者我们的细胞对产生胰岛素产生的细胞数量（2型糖尿病）的能力。这是糖尿病的治疗方法，应需要取代产生胰岛素的β细胞。多年来，不仅是从胚胎干细胞，成年干细胞或体细胞的不同来源产生β细胞的巨大努力，而且还来自胰腺中的非β细胞。一种这样的细胞类型是产生淀粉酶的胰腺腺泡细胞。这些细胞主要负责生产和分泌酶，这将帮助我们消化我们吃的食物。腺泡细胞也代表了胰腺中的大多数细胞，因此它们是新的β细胞产生的来源。在这里，我们提供的证据表明，局部粘附激酶（FAK）的遗传学以及药理学失活将胰腺腺泡细胞转化为体内胰岛素产生细胞的胰腺腺泡细胞。腺泡衍生的胰岛素产生（ADIP）细胞侵入了先前存在的胰岛，并能够恢复非自动免疫性糖尿病小鼠中的正常血糖。在当前的建议中，我们将确定ADIP细胞是否可以生存，功能性并预防自身免疫性环境中的糖尿病。该项目的总体目标是确定ADIP细胞生存并避免自身免疫攻击的能力。作为第一步，我们将研究Faki对T细胞的影响（AIM 1）。接下来，我们将确定ADIP细胞是否可以逃脱自身免疫性T细胞攻击（AIM 2）。最后，我们将比较ADIP细胞的表达曲线与常规β细胞相比（AIM 3）。这项工作是一个高优先级领域，因为它直接适用于我们对1型和2型糖尿病的全面理解和潜在治疗，并且可以对如何从腺泡细胞中产生新的功能性β细胞提供重要的理解。此过程可能会导致糖尿病反向没有胰岛移植和免疫抑制。更重要的是，如果成功的话，它应该使我们能很好地为糖尿病人类的临床试验做准备。