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

基本信息

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
项目类别：
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

项目摘要

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引起的综合征，其原因是胰岛素生成细胞数量减少（1 型糖尿病），或者细胞对胰岛素的反应能力与胰岛素生成细胞数量减少（1 型糖尿病）相结合。 2 糖尿病）因此，治疗糖尿病需要更换产生胰岛素的 β 细胞，多年来人们付出了巨大的努力来从不同来源产生 β 细胞，不仅是从胚胎干细胞，还包括成体干细胞或体细胞。细胞，也来自胰腺中的一种非β细胞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帮助我们消化所吃食物的酶。胰腺中的大多数细胞，因此它们是生成新 β 细胞的完美来源。在这里，我们提供的证据表明粘着斑激酶 (FAK) 的遗传和药理学失活都会发生转化。胰腺腺泡细胞转化为体内胰岛素产生细胞腺泡衍生的胰岛素产生细胞（ADIP）侵入预先存在的胰岛，并能够恢复非自身免疫性糖尿病小鼠的正常血糖。在自身免疫环境中能够存活、发挥功能并预防糖尿病。该项目的总体目标是确定 ADIP 细胞的存活和避免自身免疫攻击的能力。接下来，我们将确定 ADIP 细胞是否可以逃避自身免疫 T 细胞攻击（目标 2），最后，我们将比较 ADIP 细胞与常规 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 型糖尿病的全面理解和潜在治疗，并且可能为如何从腺泡细胞生成新的功能性 β 细胞提供关键的理解。无需胰岛移植和免疫抑制即可逆转糖尿病。更重要的是，如果成功，我们将为糖尿病患者的临床试验做好准备。