Objective
Our goal is to determine how the different bromodomain and extra-terminal domain (BET) protein family members contribute to the development of type I diabetes, specifically dysfunction and death of the insulin-producing β-cells of the pancreas. Drugs that target the BET protein family prevent the start and progression of type 1 diabetes in mice. How these drugs provide these benefits is unclear. We have shown that inhibiting the BET protein family with drugs reduces the β-cell response to inflammatory insult and increases β-cell function. These are potential explanations for how BET protein inhibition could prevent type 1 diabetes. The issue with using drugs that inhibit BET proteins is that most inhibit the entire family of proteins. This lack of selectivity leads to unwanted side effects, such as learning and memory defects. Since any drug used to treat type 1 diabetes could be used in children, such side effects must be avoided. Uncovering the roles of single BET proteins in producing the β-cell stress response will help develop more selective drugs for these proteins, while likely limiting adverse effects.
Background Rationale
Type 1 diabetes develops when specialized insulin-producing cells in the pancreas (β-cells) stop working and/or die. β-cells normally secrete insulin in response to high blood sugar levels, which is necessary for metabolic control in the body. Drugs that prevent decreased β-cell function and death are potential type 1 diabetes treatments.
Drugs that inhibit the bromodomain and extra-terminal domain (BET) family of proteins prevent the initiation and progression of type 1 diabetes in mice. We have shown that inhibition of BET proteins in β-cells reduces β-cell inflammation and increases β-cell function. How these drugs provide these benefits is unclear. We are determining how BET inhibition changes gene expression to increase β-cell function and decrease β-cell death.
The BET family has four members (BRD2, BRD3, BRD4, and BRDT). Each BET family member has two protein interaction segments called bromodomains. BRD2-4 are found in all mammalian cell types, including β-cells. The issue with current drugs targeting this family is that most inhibit both bromodomains of all four BET family members. This non-specific inhibition results in unwanted side effects, such as learning and memory defects. BET inhibitors could be used to treat type I diabetes in children; any side effects, especially those affecting learning, must be avoided. One way to decrease the side effects is to direct the drug to target only a single bromodomain of a single BET family member. Identifying how single bromodomains of each BET family member control the expression of genes involved in the β-cell stress response is critical to this overall goal. We anticipate that more selective drugs targeting individual BET bromodomains will increase β-cell function, decrease β-cell death, and slow or prevent the development of type 1 diabetes without side effects.
Description of Project
Specialized cells in the pancreas called β-cells produce insulin. Insulin is important because it instructs other body cells to take up sugar from the blood to use for energy. In type 1 diabetes, a patient’s immune system mistakenly attacks the cells in the pancreas that produce insulin causing decreased function and death. Consequently, the pancreas can no longer control blood sugar levels, and the body can no longer correctly produce energy. Why certain patients develop type 1 diabetes is unknown; the cause is not purely genetic. If a disease is genetic, identical twins with the same DNA will both develop the disease. However, when one identical twin has type 1 diabetes, the other twin has only a 60% chance of becoming diabetic. Therefore, factors beyond genetics are essential in determining if someone will develop type 1 diabetes. One such focus is gene expression, which is the process of how cells use their DNA as a blueprint to make proteins. During the development of type 1 diabetes, gene expression changes in the insulin-producing β-cells lead to their dysfunction and death; we will determine how specific proteins in these cells control gene expression. This knowledge will be used to design new drugs targeting these important proteins. Overall, these studies will contribute to the long-term goal of preventing or reversing type 1 diabetes.
Anticipated Outcome
During the development of type 1 diabetes, gene expression in the insulin-producing pancreatic β-cells is altered to decrease β-cell function and increase β-cell death. We will determine how members of the bromodomain and extra-terminal domain (BET) proteins family reduce β-cell response to inflammatory stimuli and increase β-cell function. The BET family has four members (BRD2, BRD3, BRD4, and BRDT), each containing two protein interaction domains called bromodomains. The BET family members use their bromodomains to bind other proteins on DNA to control gene expression. We found that inhibition of BET proteins with drugs increases the expression of β-cell function genes and reduces the expression of inflammatory genes. Therefore, BET protein inhibition has the potential to restore function and prevent the death of β-cells. We will identify how single BET proteins use their bromodomains to control gene expression in β-cells during type 1 diabetes. Non-selective inhibition of the entire BET family has undesired effects such as learning and memory problems. We expect selective inhibition of single BET bromodomains will maintain positive effects on β-cell function and inflammatory gene expression with fewer adverse effects.
Relevance to T1D
Roughly 1.6 million Americans suffer from type 1 diabetes, with an estimated cost burden of more than $16 billion. In type 1 diabetes, pancreatic β-cells, which secrete insulin in response to high blood sugar, lose proper function and die. This loss of β-cells leads to high blood sugar levels and disease development. The cause of type 1 diabetes is partially genetic; however, factors beyond DNA play a vital role. One such factor is gene expression, which is the cellular process of making proteins using DNA as a blueprint. During the development of type 1 diabetes, changes in gene expression lead to decreased β-cell function and death. Drugs that prevent these processes could treat type 1 diabetes.
Inhibition of a set of proteins called the bromodomain and extra-terminal domain (BET) family prevents type 1 diabetes in mice. We showed that inhibiting BET proteins changes gene expression in β-cells. Specifically, we see increases in expression of β-cell function genes and reduction of inflammatory gene expression. We hypothesize that BET inhibitors can control gene expression to prevent and reverse type 1 diabetes.
Despite these promising results, using BET inhibitors to treat type 1 diabetes could include harmful side effects such as learning and memory problems. These unwanted effects are because most BET inhibitors non-selectively inhibit all four BET family members. Therefore, we are determining how inhibiting individual BET bromodomains changes gene expression in β-cells. Our goal is to inform the discovery of more selective BET inhibitors that precisely control β-cell gene expression to maximize clinical benefits while avoiding side effects.