Objective
Our main objective is to understand precisely how the body's defense system, in the case of T1D, contributes to the destruction of the insulin-producing beta cells. We are particularly interested in how inflammatory signals, called cytokines, disrupt the vital functions of two key parts within these cells: the endoplasmic reticulum (ER) and the mitochondria. The ER is the cellular site where proinsulin is folded. The mitochondria are the cell's energy generators, providing the power needed for all cellular activities, including insulin production.
Specifically, we want to address the following questions: First, how do cytokines cause problems with insulin production in the beta cells? We will investigate the exact steps by which cytokines lead to misfolding of proinsulin in the ER, preventing it from becoming functional insulin. We will also examine how cytokines affect the overall environment within the ER, which is crucial for proper protein folding. Second, how do cytokines damage the mitochondria? We will determine how cytokines cause the mitochondria to lose energy and produce harmful substances called reactive oxygen species (ROS). We will also study how cytokines affect the movement and interactions of mitochondria within the cell. Third, how do cytokines disrupt the communication between the ER and mitochondria? We will focus on the contact points between these two organelles, known as mitochondria-ER contact sites (MERCs), which are essential for the exchange of calcium and other important molecules. We will investigate how cytokines affect calcium levels, ROS transfer, and the physical connection between the ER and mitochondria.
By answering these questions, we aim to uncover the precise mechanisms by which cytokines contribute to beta-cell dysfunction and destruction. This research is crucial for identifying potential targets for new therapies that can protect beta cells and prevent or slow down the progression of T1D.
Background Rationale
Traditionally, T1D has been understood as a disease where the body's immune system directly attacks and destroys the insulin-producing beta cells in the pancreas. However, recent scientific evidence suggests that the beta cells themselves may play a more active role in initiating and perpetuating this immune attack. Our research focuses on the endoplasmic reticulum (ER) and mitochondria, two critical components inside these beta cells, and how they respond to signals from the immune system. The ER is responsible for producing and folding proinsulin, the precursor to insulin, while the mitochondria provide the energy needed for all cellular functions.
To understand the complex events in the beta cells in a T1D-like condition, we have brought together a team with complementary skills. I, Anoop Arunagiri, an Assistant Professor at East Tennessee State University, have spent 15 years studying how proteins are made and folded, with a special focus on insulin production in beta cells. Dr. Amelia Linnemann, my collaborator at Indiana University, is an expert in how beta cells react to stress, which is a crucial factor in T1D. Together, we are looking at how signals from the immune system disrupt ER and mitochondrial health, as well as the communication between these two in beta cells.
The rationale for this research is based on several key points. First, we need to understand exactly how the ER and mitochondria communicate with each other and how this communication breaks down in T1D. This involves studying how the cells respond to inflammatory signals from the immune system and how these responses contribute to the destruction of beta cells. By investigating the interactions between these organelles, we can gain a deeper understanding of the molecular events that lead to beta-cell loss. Second, by understanding the precise mechanisms of cellular damage, we can identify new targets for therapeutic intervention. This will allow us to develop strategies to protect beta cells from destruction and prevent the progression of T1D. Third, we aim to develop better treatments that target the underlying causes of beta-cell destruction, rather than simply managing the symptoms of high blood sugar. Current treatments primarily focus on replacing the missing insulin, but they do not prevent the ongoing destruction of beta cells.
Our research aims to provide a comprehensive understanding of how beta cells are lost in T1D, paving the way for the development of effective therapies that can preserve beta-cell function and ultimately improve the lives of individuals living with this disease. We believe that by focusing on the interplay between the ER and mitochondria, we can find new and innovative ways to combat T1D.
Description of Project
Type 1 Diabetes (T1D) is a serious and lifelong condition where the body's own defense system, which is meant to protect us from harmful invaders like bacteria and viruses, mistakenly attacks and destroys the cells that make insulin. These cells, called beta cells, are located in the pancreas, an organ that helps with digestion and blood sugar control. Insulin is a crucial hormone that acts like a key, allowing the sugar from our food to enter our cells and be used for energy. When beta cells are destroyed, the body can no longer produce insulin, leading to high levels of sugar in the blood. This high blood sugar, if left unchecked, can cause serious damage to various parts of the body, including the heart, kidneys, eyes, and nerves.
For a long time, scientists believed that the immune system was solely responsible for attacking the beta cells in T1D. However, recent research suggests that the beta cells themselves might play a role in triggering this attack. When these cells experience stress, they can release signals that attract the attention of the immune system, almost like sending out a distress call. Our research focuses on two important parts inside these beta cells: the endoplasmic reticulum (ER) and the mitochondria. The ER is the cell's protein factory, where proinsulin, the precursor to insulin hormone, is made and meticulously folded into its precise three-dimensional structure. This proper folding is critical for proinsulin to be converted into functional insulin. The mitochondria, on the other hand, are the cell's power plants, generating the energy required for all cellular processes, including insulin production and secretion.
In T1D, the signals sent out by the immune system disrupt the normal functioning of the ER and mitochondria. This disruption is expected to lead to problems with proinsulin folding in the ER and damages the mitochondria. We are using advanced microscopy and biochemical techniques to see exactly how these signals cause this damage. By understanding this process, we hope to identify new ways to protect the beta cells from destruction. Ultimately, our goal is to develop treatments that can stop T1D and improve the quality of life for people living with this challenging disease. We believe that by focusing on the interactions between the ER and mitochondria in beta cells, we can find new and effective ways to combat T1D and prevent its devastating long-term effects.
Anticipated Outcome
We anticipate that our research will provide a detailed and comprehensive understanding of how inflammatory signals from the immune system disrupt the communication between the endoplasmic reticulum (ER) and mitochondria in beta cells, leading to cellular dysfunction in T1D. We expect to demonstrate a clear sequence of molecular events that contribute to the destruction of these vital cells.
Specifically, we expect to achieve the following outcomes:
(1) We will identify the precise molecular mechanisms by which inflammatory signals cause problems with proinsulin folding in the ER. This will involve characterizing the specific signaling pathways and molecules involved in this process. We anticipate demonstrating how these signals lead to misfolding of proinsulin, preventing it from becoming functional insulin.
(2) We will show exactly how inflammatory signals damage the mitochondria. This will include analyzing changes in the movement and interactions of mitochondria within the cell, as well as the production of harmful reactive oxygen species (ROS).
(3) We will reveal how inflammatory signals disrupt the communication between the ER and mitochondria. This will involve studying the contact points between these two organelles, known as mitochondria-ER contact sites, which are essential for the exchange of calcium and other important molecules.
(4) We will use advanced microscopy techniques to visualize and quantify the structural changes in the ER and mitochondria caused by cytokines. This will provide detailed information about how these signals alter the shape and organization of these organelles.
These findings will provide a solid foundation for the development of effective therapies that can halt or reverse the progression of T1D. By elucidating the precise mechanisms of cellular damage, we hope to identify new targets for therapeutic intervention and ultimately improve the lives of individuals living with this challenging disease.
Relevance to T1D
Type 1 Diabetes (T1D) is a devastating autoimmune disease where the body's defense system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. These beta cells are the only cells in the body that can produce insulin, a hormone essential for regulating blood sugar. Without insulin, sugar builds up in the blood, leading to high blood sugar levels and serious health problems over time, including heart disease, kidney damage, vision loss, and nerve damage.
Our research focuses on understanding how inflammatory signals, called cytokines, affect two crucial parts inside these beta cells: the endoplasmic reticulum (ER) and the mitochondria. The ER is like a factory where proinsulin, the precursor to insulin, is made, and the mitochondria are like the cell's power plants, providing the energy needed for all cellular functions. Both the ER and mitochondria are essential for the survival and proper function of beta cells.
Our research is highly relevant to T1D for several reasons. First, we are trying to understand the exact molecular events that lead to the destruction of beta cells. By investigating how inflammatory signals affect the ER and mitochondria, we are gaining a deeper understanding of the processes that cause beta-cell dysfunction and death. Second, we are focusing on the communication between the ER and mitochondria, which is a critical but often overlooked aspect of T1D. By studying how inflammatory signals disrupt this communication, we can identify new targets for therapeutic intervention. Third, we aim to identify new therapies that can protect beta cells from destruction. Current treatments primarily focus on replacing the missing insulin, but they do not prevent the ongoing destruction of beta cells. Our research aims to develop therapies that can preserve or restore beta-cell function, potentially halting or even reversing the progression of T1D. This is crucial because it addresses the root cause of the disease, rather than just managing its symptoms. By finding ways to protect and revitalize the insulin-producing cells, we hope to move beyond lifelong insulin injections and towards a future where individuals with T1D can live healthier, more independent lives.