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: 10374892
• 负责人: FARZAD ESNI
• 金额: $ 23.73万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374892
• 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.

糖尿病是一种由胰岛素生成细胞数量减少(1型糖尿病)或我们的细胞对胰岛素的反应能力结合胰岛素生成细胞数量下降(2型糖尿病)而导致的高血糖水平的综合征。因此，治疗糖尿病的方法应该是替换产生胰岛素的β细胞。多年来，人们做出了巨大的努力，从不同的来源产生β细胞，不仅来自胚胎干细胞，成体干细胞或体细胞，也来自驻留在胰腺的非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。这些细胞主要负责产生和分泌酶，帮助我们消化我们所吃的食物。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细胞生成的完美来源。在这里，我们提供了证据表明，在体内，粘着斑激酶(FAK)的遗传和药物失活都能将胰腺腺泡细胞转化为胰岛素产生细胞。腺泡来源的胰岛素产生(ADIP)细胞侵入先前存在的胰岛，并能够在非自身免疫性糖尿病小鼠中恢复正常血糖。在目前的提案中，我们将确定脂肪细胞是否能够在自身免疫环境中存活、发挥功能并预防糖尿病。该项目的总体目标是确定脂肪细胞存活和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(目标1)。接下来，我们将确定脂肪细胞是否能够逃脱自身免疫T细胞的攻击(目标2)。最后，我们将比较ADIP细胞和正常β细胞的表达谱(目标3)。这项工作是一个高度优先的领域，因为它直接适用于我们对1型和2型糖尿病的充分理解和潜在的治疗，并可能为如何从腺泡细胞生成新的功能β细胞提供关键的理解。这一过程可以在不进行胰岛移植和免疫抑制的情况下逆转糖尿病。更重要的是，如果成功，它将使我们为糖尿病患者的临床试验做好准备。