We propose an industry collaboration between investigators in the University of Florida Diabetes Institute and an industry partner, Immunocore Ltd. Immunocore utilizes its T cell receptor (TCR) technology to generate tissue-targeted immune suppressant bispecifics called ImmTAAI (Immune modulating monoclonal TCR Against Autoimmune Disease) molecules. ImmTAAIs consist of a high affinity TCR-based targeting domain specific for […]
Year: 2020
Longitudinal Determination of Islet Specific protein expression in T1D
Pandion Therapeutics is a biotechnology company developing bifunctional protein therapeutics to achieve localized immunomodulation at the site of disease for durable, tissue-specific treatment of patients with autoimmune and inflammatory disease and organ transplant. Our localized approach represents a significant change from the systemic immunosuppression of conventional medicines. Through tissue-specific therapeutic targeting, Pandion’s approach has the […]
Functional Role of CADM1 during Type 1 Diabetes Pathogenesis
Type 1 diabetes (T1D) is characterized by the hyperglycemia resulting from the autoimmune destruction of the insulin-expressing β-cells of the pancreas. As the prevalence of the disease continues to increase worldwide, it remains imperative to identify therapeutic strategies that can (1) preserve pancreatic beta-cell mass and function and (2) prevent the immune response that initiates […]
Innate immunity and diabetes
Although T1D is considered to be mainly a T-cell mediated and a beta-cell specific disease we have generated over the years the hypothesis (and some supporting data) that innate immunity is also key in disease initiation and that T1D might be a disease of the whole pancreas that manifests in autoimmunity to beta cells. Our […]
Investigating the role of aggregation-prone proteins in pancreatic beta cell function and health
Almost 20% of the chromosomal regions associated with the risk of developing of Type 1 diabetes (T1D) identified to date,have no identified candidate causal gene. Often, this is because the genes in those regions have no known roles in the immune system, reflecting the classical view that T1D is caused by the autoimmune destruction of […]
Analysis of major digestive enzymes expression in human pancreas
Type I diabetes is characterized by significant loss of beta cells and decrease in pancreatic weight. It is widely accepted that decline of pancreatic weight is attributed to acinar atrophy which in turn could lead to pancreatic exocrine insufficiency frequently found in diabetic patients. However, the fact that the exocrine pancreas is affected in patients […]
Beta Cell Senescence and T1D
Type 1 diabetes (T1D) results from an autoimmune disorder characterized by T-cell-mediated destruction of pancreatic beta cells. While the role of auto-reactive T cells in targeting beta cells has been well defined, the pathological mechanisms operating in beta cells remains poorly understood. To investigate beta cell stress responses during disease progression but before diabetes onset, […]
Microtubule-associated protein TAU and the Islets of Langerhans
Tau is one of the most important known molecules for microtubular dynamic and trafficking within the cells. In neurogenerative disorders such as Alzheimer disease, the tau becomes hyperphosporylated and form insoluble intracellular protein aggregates leading to upregulation of unfolded protein response. At the same time, patients with Alzheimer’s disease show impaired glucose metabolism. Moreover, both […]
Decoding and Reprogramming Stem-Like Progenitor CD8 T cells Driving Type 1 Diabetes
The pathogenesis of T1D is complex and involves many distinct immune populations. Autoreactive CD8 T cells play a major role as the ultimate mediators of beta cell destruction in the pancreas, leading to the loss of glucose homeostasis. However, many aspects of the programming and regulation of CD8 T cells mediating autoimmunity remain enigmatic. Utilizing […]
Probing the normal human pancreatic and islet matrisome throughout development
Diabetes is a major world health problem, affecting millions of Americans, costing billions of dollars in treatment, and causing major late-stage health complications and death. Despite the promise of stem cell therapies for diabetes, the field of beta cell differentiation has not yet reached clinical application, mainly due to the lack of mature function and […]
Identification of novel monoclonal antibodies directed against pancreatic endocrine cell types for in vitroand in vivo analysis and targeting
Diabetes mellitus is a multifactorial disease characterized by progressive loss or dysfunction of the insulin-producing beta cells in the pancreas that leads to chronic hyperglycemia, systemic metabolic complications and multi-organ damages. Nowadays, no current treatments can stop or reverse the disease progression, apart bariatric surgery and human islet transplantation. Therefore, intensive efforts in the field […]
Transcription factor:coregulator interactions are compromised in islet cells under diabetogenic conditions
Beta cell dysfunction occurs in the early stages of type 1 (T1D) and type 2 diabetes (T2D) development. Strategies to improve outcomes for the mounting number of diabetic patients requires understanding the complex programs that coordinate a proper insulin release in response to changing blood glucose levels and how these mechanisms falter in diabetogenic settings. […]
Evaluation of Fatty Acid Levels in Human Pancreatic Tissue using Imaging Mass Spectrometry
Alterations in metabolism are known to play profound roles inthe health ofindividuals with type 1 diabetes (T1D). These alterations lead to disruptions in cell structure, signaling, and energy homeostasis. While most studies focus on identifying genetic or protein signatures of disease, the metabolic profile is a far more dynamic, sensitive, and rapidly-responding molecular measure of […]
Insulin Receptor on T cells in T1D
T cell movement into the islets in the pancreas, is a hallmark feature of Type 1 diabetes (T1D) that has been demonstrated on autopsy in human pancreas specimens and in mouse models of T1D such as the non-obese diabetic (NOD) mouse3-8. By determiningthe role that insulin receptor (IR)plays in this movement of the T cells […]
Credentialing immunotherapy targets in islet tissues with insulitis
Sanofi is developing strategies to control beta cell destruction in type 1 diabetes (T1D) through immunotherapy. Strategies could include targeting specific molecules on cells that may be of importance in disease pathogenesis. Such approaches are in progress and candidate molecular targets of potential interest have been identified. As part of the next steps, our goal […]
Validation of blood – derived single cell gene expression signature in peri – pancreatic lymph nodes of Type 1 Diabetes subjects
Type 1 diabetes (T1D) is an organ specific autoimmune disease resulting in an immune-mediated destruction of insulin-secreting beta cells. The etiology of T1Dis puzzled by a multifaceted interaction of environmental, genetic and epigenetic factors leading to variousendotypesof the disease. Fine mapping of T1D-associated genetic variants with cell-specific epigenetic markers or expression quantitative traits (eQTLs) indicates […]
Conversion of human acinar cells into insulin – producing cells
Reprogramming of acinar cells toward functional β-like cells would offer an abundant and autologous source of insulin-producing cells. The current literature suggeststhat manipulation of genetic factors,in combination with cytokines or small molecules targeting specific pathways and the epigenetic machinery in humans,may eventually yield functional acinar-derived β-like cells. Our preliminary datashowthat treatment of adult mice with […]
Meta – proteomic biomarkers in stool for prediction of islet autoimmunity progression
Type 1 diabetes (T1D) is increasing around the world due to unknown changes in our lifestyle. One factor that may drive this change is the bacteria in our intestines. These bacteria interact potently with our immune system and metabolism. We have shown that changes in intestinal and pancreatic proteins found in stool are associated with […]
The role inflammatory signaling crosstalk on human exocrine and beta cells
There is increasing evidence for cross-talk between the islet and exocrine compartments of the pancreas. Diabetes is a risk factor for exocrine atrophy, pancreatitis, and pancreatic cancer. Conversely, pancreatitis is a risk factor for diabetes. Until now our ability to study human endocrine and exocrine cells has been limited to isolated islets and isolated exocrine […]
ORIGINAL: Proinsulin processing and presentation in human type 1 diabetes: a beta cell perspective ADDENDUM: Proinsulin processing and presentation in human type 1 diabetes: a beta cell perspective –T cell perspective
ORIGINAL: Type 1 diabetes (T1D) is an autoimmune disease in which clinical symptoms arise as a result of insulin deficiency. While genetic and environmental factors contribute to the disease, in recent years it has become increasingly evident that beta cells might be contributing to their own destruction and might have an active role in type […]
nPOD Slice Manuscript Publication
Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis. Panzer JK, Hiller H, Cohrs CM, Almaça J, Enos SJ, Beery M, Cechin S, Drotar DM, Weitz JR, Santini J, Huber MK, Muhammad Fahd Qadir M, Pastori RL, Domínguez-Bendala J, Phelps EA, Atkinson MA, Pugliese A, Caicedo A, Kusmartseva I, […]
Manipulating DNA damage-response signaling for the treatment of type 1 diabetes
As T cell toggle through their various life cycle, certain distinct biological changes occur that can be specifically targeted with small molecule drugs to target these cells for cell death. This is particularly true of activated autoreactive T cells. We have developed a combination of small molecular drugs that can target activated T cells and […]
Changes in human islet microvasculature during the progression of type 1 diabetes
Endocrine cells in pancreatic islets are embedded in a network of microvessels that regulate islet blood flow and hormone secretion. It is still unknown what happens to the islet microvasculature in type 1 diabetes (T1D), despite being the site of immune cell recruitment and infiltration. The microvasculature consists of capillary tubes made of a thin […]
Regulation of Islet Autophagy in Type 1 Diabetes
Oxidative stress occurs when increased production of cellular oxidants (e.g. Reactive Oxygen Species, or ROS) is not compensated for by an increase in cellular antioxidants/antioxidant enzymes. A considerable body of evidence supports the conclusion that oxidative stress is a common feature of type 1 diabetes (T1D), and that the process of autophagy plays a key […]
Single cell analysis of the human pancreas in type 1 diabetes
Type 1 diabetes (T1D) is an autoimmune disorder that affects 1.25 million individuals in the US and for which there is no known cause or cure. T1D is characterized by autoimmune destruction of insulin- producing beta cells in the pancreatic islets. The pancreas consists of multiple different cell-types relevant to diabetes pathogenesis including endocrine (beta, […]
Assessing heterogeneity of DR3 haplotype risk in type 1 diabetes
We have discovered a new DNA variation that we think may affect T1D risk in individuals carrying a particular type of HLA-DRB1 gene. We aim to look at particular nPOD samples with that HLA genotype to see if they contain our newly discovered variant. If so, we will be able to design a future project […]
FOXO1 inhibition-mediated reprogramming of b-like cells in gastrointestinal tissues from type 1 diabetic donors
Genetic inactivation of the nuclear transcription factor Forkhead box protein O1 (FOXO1) in mice in specific intestinal endocrine progenitor cells reprograms them into glucose-responsive insulin- producing (beta-like) cells, raising the promise that the gut can serve as an endogenous source for beta cell replacement. This phenomenon has also been demonstrated in vitro in cells derived […]
Validating KIRAs as β-cell-sparing drugs in islets from human patients with T1D
Our lab has been focusing for many years on the intrinsic stress experienced by pancreatic islet β-cells, which (even in healthy states) live under a strict metabolic mandate to continuously produce and secrete insulin at intensely high rates that predispose these professional secretory cells to secretory exhaustion. β-cells evolved a high-capacity endoplasmic reticulum (ER) organelle […]
The cellular distribution of Golli protein in human pancreatic islets
The objective of this application is to determine the cellular distribution of Golli protein in human pancreatic islets. Golli (gene expressed in oligodendrocyte lineage) is an alternatively spliced product of myelin basic protein (MBP) gene featured by the presence of a unique Golli domain which contains a 133-amino-acid sequence fused in the N-terminal of classic […]
Modulation of autoimmune diabetes by natural antibodies specific for N-acetyl-D- glucosamine
The focus of our research project is to improve the understanding of how antigenic stimulation of the B lymphocyte repertoire development during early life may protect from Type 1 Diabetes (T1D). Specifically, we are investigating how exposure to the common pathogen Group A Streptococcus promotes the formation of a T1D-suppressive natural antibody repertoire. Exposure to […]
Dissecting the role intestinal NK cells play in T1D pathogenesis
There is conflicting information regarding the role of natural killer (NK) cells in the development of Type 1 Diabetes (T1D). NK cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of T1D in at least a portion of patients. NK cells of […]
Transcriptional heterogeneity in the intact human pancreas
Pancreatic beta cells have been shown to be heterogeneous at multiple levels. However, spatially interrogating transcriptional heterogeneity in the intact tissue has been challenging. We developed an optimized protocol for single-molecule transcript imaging in the intact pancreas and used it to identify a sub-population of “extreme” beta cells with elevated mRNA levels of insulin and […]
High-resolution mapping of the human pancreatic magnetic resonance landscape
Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) both detect signals from atomic nuclei and can be performed together in conventional clinical MRI scanners. MRI provides the anatomical information, after which MRS scanning can provide biochemical information on the constituents within a region of interest. MRS has been used in clinical settings to study […]
Beta cell DNA double strand breaks in Type 1 diabetes
Emerging evidence suggests beta cell dysfunction and failure precede autoimmune destruction during the development of type 1 diabetes, but the underlying mechanisms are not known. Defining and targeting the changes leading to impaired beta cell function may lead to clinical improvement and prolonged honeymoon period. We have recently discovered that in type 2 diabetes, beta […]
Characterising the organisation of the gut associated lymphoid tissue in type 1 diabetes and tracking T and B cell receptor clonotype / isotype usage and islet antigen-specific lymphocytes across tissues in the nPOD resource.
The intestinal microbiome plays an essential role in host health, where microbial communities have immune-modulating activity and impact on regulatory immune cell compartmentalisation in the gut associated lymphoid tissues. Increasing evidence points to a dysfunctional relationship between the microbiome and host tissues in individuals who develop type 1 diabetes (T1D). Alterations in gut microbial composition […]
Role of Rab1A in Diabetes Mellitus
We previously identified the Rab1A small GTPase as a conserved activator of mTORC1 in response to amino acid (AA) stimulation in yeast and mammalian cells. To better understand the physiological function of Rab1A- mTORC1 signaling in vivo, we genetically engineered conditional Rab1A knockout (Rab1A-KO) in mice. We found that tamoxifen-induced Rab1A knockout in young adult […]
Harnessing the power of beta cell regeneration to treat diabetes
Approximately 1 in 11 people worldwide is afflicted by diabetes, a disease caused by a shortage of beta cells. The current standard of care for patients with severe diabetes is insulin therapy or pancreatic islet transplantation. However, insulin therapy requires frequent insulin injection, detailed dose calibration and close monitoring of blood glucose; for islet transplantation, […]
IGF receptor-like 1 and 2, new therapeutic targets for increasing insulin sensitivity and beta cell health
Diabetes mellitus is a complex and multifactorial disease characterized by progressive loss or dysfunction of the insulin-producing beta cells in the pancreas. This results in chronic hyperglycemia and systemic metabolic complications and, in the long-term, in multi-organ damages; together, these complications create enormous medical and social burdens as well as causing premature deaths. Today, over […]
Identification of HERV-W copies and insertion sites associated with T1D in human genomes
T1D etiology is not clearly understood, but it lies at crossroads between genetic predisposition and environmental factors. Research on the human genome has so far identified numerous candidate sequences as genetic risk factors, most notably within the HLA (Human Leucocyte Antigen) region. However, an important part of the human genome has been neglected in the […]
CD3+CD56+ T lymphocytes, as novel T1D biomarker
Type 1 Diabetes (T1D) is a disease characterized by a lymphocyte-mediated destruction of insulin-producing beta-cells in genetically susceptible individuals. It has been demonstrated that lymphocytes with regulatory properties are essential for the maintenance of tolerance against self-tissues (pancreas) and alterations in the number and functions of these cells have been correlated with the break of […]
NIH RFA for T1D Research
NIH RFA 19-026: New Investigator Gateway Awards for Collaborative T1D Research ** Letter of Intent Due Date(s): February 25, 2020 & October 3, 2020 ** NIH has issued a “New Investigator Gateway Awards for Collaborative T1D Research” Funding Initiative. This initiative is similar to our internal HIRN New Investigator Initiative we held a few years ago […]