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The role of Maf transcrition factors in type 1 diabetes

Singh, Tania (2013) MOBM19 20122
Degree Projects in Molecular Biology
Abstract
Abstract
Type 1 Diabetes is an autoimmune disease characterized by chronic hyperglycemia that results from a selective loss of insulin secreting pancreatic beta cells. The aetiology of T1D often involves both genetic and environmental factors like viral infections. In T1D, insulin is regarded as primary autoantigen that becomes one of the targets of autoimmune attack and is found to be expressed in both pancreatic islets and the thymus. Mechanisms behind the induction of central tolerance in governed by the thymus as it expresses tissue specific self-antigens. Here, we study the role of Maf transcription factors in T1D susceptibility due to its widespread role in transcriptional regulation of insulin and other beta cell factors that also... (More)
Abstract
Type 1 Diabetes is an autoimmune disease characterized by chronic hyperglycemia that results from a selective loss of insulin secreting pancreatic beta cells. The aetiology of T1D often involves both genetic and environmental factors like viral infections. In T1D, insulin is regarded as primary autoantigen that becomes one of the targets of autoimmune attack and is found to be expressed in both pancreatic islets and the thymus. Mechanisms behind the induction of central tolerance in governed by the thymus as it expresses tissue specific self-antigens. Here, we study the role of Maf transcription factors in T1D susceptibility due to its widespread role in transcriptional regulation of insulin and other beta cell factors that also act as islet autoantigens. Recent data suggest that variations in the Maf levels may cause susceptibility to viral infections that potentially trigger autoimmune response to self-tissues. Our previous studies have shown that deficiency of Maf transcription factors leads to the development of inflammation adjacent to islets. Infiltration of immune cells can be triggered by defects in the systemic immune system and/or in beta cells. The first project was designed to distinguish between these possibilities and evaluate the effect of changes in Maf levels on the development of autoimmune reaction. Here we examine if the T1D symptoms observed in the Maf mutant mice are caused by a systemic or local defect in beta cells. The second project focuses on defining the specific roles of Maf in intrathymic regulation of major autoantigens at the E18.5.

Popular science sumary:

More than 180 million people worldwide suffer from diabetes and the numbers of cases are expected to double by 2030 according to WHO estimates. Diabetes mellitus is a life-long incurable disease characterized by high blood sugar levels caused by insulin deficiency that leads to serious health complications like cardiovascular, gastrointestinal defects etc. Insulin is a hormone produced by islet beta (β) cells of the pancreas and plays a central role in glucose metabolism by facilitating its storage in the liver. In type 1 diabetes (T1D), β cells are selectively destroyed by an autoimmune attack. Among many innate and adaptive immune cells involved in T1D, T cells are known to specifically play an aggressive role in β cell damage by recognizing self-body components/autoantigens like insulin.
To be able to develop or design possible diabetes treatment strategies like generating β cell sources through de novo β cell differentiation, it becomes important to understand the molecular pathways underlying β cell development and function, as defects in its function will ultimately affect individuals to maintain healthy glycemic control. Understanding of the immune responses against β cells in both T1D and health status of isolated islets used for transplantation and characterization of islet cells enriched transcription factors (TFs) involved in β cell development, maturation and function will be of high value. In the present project, we study the role of Maf TFs: MafA and MafB in T1D susceptibility due to its widespread role in islet cell differentiation, maturation, insulin regulation etc. Also recent studies have shown that variations in Maf levels may enhance the risk of viral infections and produce impairment in regulation of intra-thymic T1D autoantigen levels that may potentially trigger the autoimmune response against β cells.
Our previous studies have shown that deficiency of Maf TFs leads to the development of T1D like symptoms (inflammation) adjacent to islets. Infiltration of immune cells may be triggered by defects in the immune system and/or in islet β cells or both due to the absence of Maf proteins. The first project was studied to distinguish between these possibilities with the use of two transgenic mouse model systems and to evaluate the effect of Maf TFs deficiency on the development of autoimmune reaction. Immunohistochemistry analysis was performed on 6 month old Maf mutant pancreata sections with CD3, Insulin and DAPI staining for detection of T cells, islets and nucleus, respectively. The second project focused on defining the specific roles of Maf TFs in intrathymic regulation of autoantigens marked in T1D. Q-PCR analysis to detect mRNA expression of MafA, MafB and major T1D autoantigens were studied on thymic cDNA of E18.5 Maf mutants. Overall results from both projects suggests that alterations in expression of Maf TFs may increase the susceptibility for T1D development by producing defects in the immune system that may lead to an autoimmune destruction of β cells.

Advisor: Isabella Artner (Associate professor)
Master´s Degree Project: 30 credits in Molecular Genetics, 2013
Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Singh, Tania
supervisor
organization
course
MOBM19 20122
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
3626405
date added to LUP
2013-03-26 16:04:08
date last changed
2013-03-26 16:04:08
@misc{3626405,
  abstract     = {Abstract
Type 1 Diabetes is an autoimmune disease characterized by chronic hyperglycemia that results from a selective loss of insulin secreting pancreatic beta cells. The aetiology of T1D often involves both genetic and environmental factors like viral infections. In T1D, insulin is regarded as primary autoantigen that becomes one of the targets of autoimmune attack and is found to be expressed in both pancreatic islets and the thymus. Mechanisms behind the induction of central tolerance in governed by the thymus as it expresses tissue specific self-antigens. Here, we study the role of Maf transcription factors in T1D susceptibility due to its widespread role in transcriptional regulation of insulin and other beta cell factors that also act as islet autoantigens. Recent data suggest that variations in the Maf levels may cause susceptibility to viral infections that potentially trigger autoimmune response to self-tissues. Our previous studies have shown that deficiency of Maf transcription factors leads to the development of inflammation adjacent to islets. Infiltration of immune cells can be triggered by defects in the systemic immune system and/or in beta cells. The first project was designed to distinguish between these possibilities and evaluate the effect of changes in Maf levels on the development of autoimmune reaction. Here we examine if the T1D symptoms observed in the Maf mutant mice are caused by a systemic or local defect in beta cells. The second project focuses on defining the specific roles of Maf in intrathymic regulation of major autoantigens at the E18.5.

Popular science sumary:

More than 180 million people worldwide suffer from diabetes and the numbers of cases are expected to double by 2030 according to WHO estimates. Diabetes mellitus is a life-long incurable disease characterized by high blood sugar levels caused by insulin deficiency that leads to serious health complications like cardiovascular, gastrointestinal defects etc. Insulin is a hormone produced by islet beta (β) cells of the pancreas and plays a central role in glucose metabolism by facilitating its storage in the liver. In type 1 diabetes (T1D), β cells are selectively destroyed by an autoimmune attack. Among many innate and adaptive immune cells involved in T1D, T cells are known to specifically play an aggressive role in β cell damage by recognizing self-body components/autoantigens like insulin.
To be able to develop or design possible diabetes treatment strategies like generating β cell sources through de novo β cell differentiation, it becomes important to understand the molecular pathways underlying β cell development and function, as defects in its function will ultimately affect individuals to maintain healthy glycemic control. Understanding of the immune responses against β cells in both T1D and health status of isolated islets used for transplantation and characterization of islet cells enriched transcription factors (TFs) involved in β cell development, maturation and function will be of high value. In the present project, we study the role of Maf TFs: MafA and MafB in T1D susceptibility due to its widespread role in islet cell differentiation, maturation, insulin regulation etc. Also recent studies have shown that variations in Maf levels may enhance the risk of viral infections and produce impairment in regulation of intra-thymic T1D autoantigen levels that may potentially trigger the autoimmune response against β cells.
Our previous studies have shown that deficiency of Maf TFs leads to the development of T1D like symptoms (inflammation) adjacent to islets. Infiltration of immune cells may be triggered by defects in the immune system and/or in islet β cells or both due to the absence of Maf proteins. The first project was studied to distinguish between these possibilities with the use of two transgenic mouse model systems and to evaluate the effect of Maf TFs deficiency on the development of autoimmune reaction. Immunohistochemistry analysis was performed on 6 month old Maf mutant pancreata sections with CD3, Insulin and DAPI staining for detection of T cells, islets and nucleus, respectively. The second project focused on defining the specific roles of Maf TFs in intrathymic regulation of autoantigens marked in T1D. Q-PCR analysis to detect mRNA expression of MafA, MafB and major T1D autoantigens were studied on thymic cDNA of E18.5 Maf mutants. Overall results from both projects suggests that alterations in expression of Maf TFs may increase the susceptibility for T1D development by producing defects in the immune system that may lead to an autoimmune destruction of β cells.

Advisor: Isabella Artner (Associate professor)
Master´s Degree Project: 30 credits in Molecular Genetics, 2013
Department of Biology, Lund University},
  author       = {Singh, Tania},
  language     = {eng},
  note         = {Student Paper},
  title        = {The role of Maf transcrition factors in type 1 diabetes},
  year         = {2013},
}