Objective
This project will identify new molecular mechanisms that contribute to type 1 diabetes (T1D) pathophysiology and test novel therapeutic strategies to improve β cell function to prevent or delay T1D. We will also test how biomarkers of β cell mitochondrial dysfunction can be leveraged alone and in combination with other circulating markers to predict the development of T1D in those at-risk for the disease.
Background Rationale
T1D results from immune-mediated destruction of the insulin-producing pancreatic β cells, leading to severe complications and reduced life expectancy. The only approved treatment for T1D is life-long administration of insulin; however, less than a quarter of individuals with T1D meet their glycemic goals with current therapies. A new disease-modifying therapy has been approved to delay the onset of T1D, but there is still no cure for the disease, and not all patients respond to this treatment. In addition, there are no available disease-modifying therapies for people who progress to a clinical diagnosis of T1D. These findings underscore the need to better understand how and why β cells are destroyed during T1D and to develop novel markers of disease progression to identify at-risk individuals and prevent or delay disease onset.
Recent data from our lab and others show that β cells play an active role in the pathogenesis of T1D, rather than simply being “innocent bystanders” to autoimmune attack. During the development of T1D, stressed and dying β cells generate signals that amplify immune responses. Interrupting this harmful interaction between the immune and endocrine cells during the development of T1D could have important implications for disease-modifying therapies. Our previous studies in mouse models and human tissues indicate that dysregulated endoplasmic reticulum (ER) and mitochondrial calcium (Ca2+) homeostasis in the β cell may contribute to T1D. Here, we will address the following questions: 1) is the health of mitochondria within β cells is a key determinant of whether these cells survive or become targets of the immune system? 2) can we target β cell mitochondrial health as a therapeutic approach for preventing T1D? and 3) can circulating signatures of β cell mitochondrial health serve as early markers of T1D risk?
Description of Project
Objective:
This project will identify new molecular mechanisms that contribute to type 1 diabetes (T1D) pathophysiology and test novel therapeutic strategies to improve β cell function to prevent or delay T1D. We will also test how biomarkers of β cell mitochondrial dysfunction can be leveraged alone and in combination with other circulating markers to predict the development of T1D in those at-risk for the disease.
Background/Rationale:
T1D results from immune-mediated destruction of the insulin-producing pancreatic β cells, leading to severe complications and reduced life expectancy. The only approved treatment for T1D is life-long administration of insulin; however, less than a quarter of individuals with T1D meet their glycemic goals with current therapies. A new disease-modifying therapy has been approved to delay the onset of T1D, but there is still no cure for the disease, and not all patients respond to this treatment. In addition, there are no available disease-modifying therapies for people who progress to a clinical diagnosis of T1D. These findings underscore the need to better understand how and why β cells are destroyed during T1D and to develop novel markers of disease progression to identify at-risk individuals and prevent or delay disease onset.
Recent data from our lab and others show that β cells play an active role in the pathogenesis of T1D, rather than simply being “innocent bystanders” to autoimmune attack. During the development of T1D, stressed and dying β cells generate signals that amplify immune responses. Interrupting this harmful interaction between the immune and endocrine cells during the development of T1D could have important implications for disease-modifying therapies. Our previous studies in mouse models and human tissues indicate that dysregulated endoplasmic reticulum (ER) and mitochondrial calcium (Ca2+) homeostasis in the β cell may contribute to T1D. Here, we will address the following questions: 1) is the health of mitochondria within β cells is a key determinant of whether these cells survive or become targets of the immune system? 2) can we target β cell mitochondrial health as a therapeutic approach for preventing T1D? and 3) can circulating signatures of β cell mitochondrial health serve as early markers of T1D risk?
Anticipated Outcomes:
The work proposed here will: 1) define the relationship between alterations in ER and mitochondrial Ca2+ and their roles in T1D; 2) determine how modulation of ER and mitochondrial Ca2+ impact β cell pathways that activate the immune system; and 3) define new clinically-significant biomarkers that identify at-risk individuals. Furthermore, we will use mouse models and human cells to determine whether therapeutics that block inflammatory signaling and impaired β cell mitochondrial health can preserve β cells during T1D.
Relevance to Type 1 Diabetes:
There is a critical need to understand the active role that β cells play in the development of T1D. To date, most research and clinical trials in the field have focused on targeting the immune system, and there are no approved therapies to support β cell health in T1D. Exciting new data from our lab and others show that β cell stress and dysfunction play a key role in “inviting” immune attack and destruction during T1D. Our novel studies will lead to a greater understanding of the interaction between β cells and the immune system during T1D and define new biomarkers that reflect the health status of the β cell and better identify at-risk individuals. Together, these findings will lead to new avenues for clinical trials that support β cell health during T1D.
Anticipated Outcome
The work proposed here will: 1) define the relationship between alterations in ER and mitochondrial Ca2+ and their roles in T1D; 2) determine how modulation of ER and mitochondrial Ca2+ impact β cell pathways that activate the immune system; and 3) define new clinically-significant biomarkers that identify at-risk individuals. Furthermore, we will use mouse models and human cells to determine whether therapeutics that block inflammatory signaling and impaired β cell mitochondrial health can preserve β cells during T1D.
Relevance to T1D
There is a critical need to understand the active role that β cells play in the development of T1D. To date, most research and clinical trials in the field have focused on targeting the immune system, and there are no approved therapies to support β cell health in T1D. Exciting new data from our lab and others show that β cell stress and dysfunction play a key role in “inviting” immune attack and destruction during T1D. Our novel studies will lead to a greater understanding of the interaction between β cells and the immune system during T1D and define new biomarkers that reflect the health status of the β cell and better identify at-risk individuals. Together, these findings will lead to new avenues for clinical trials that support β cell health during T1D.