Oxidative stress and mitochondrial dysfunction have been associated with a wide range of neurodegenerative diseases and metabolic disorders such as diabetes. A major public health problem is the increase in the incidence of obesity-related diseases, such as diabetes and its complications and the increased incidence of neurodegenerative diseases, for example Parkinson's and Alzheimer's diseases in the aging population. Therapeutic and preventive strategies to reduce the complications of diabetes and to treat neurodegenerative diseases are urgently needed. Several lines of evidence indicate that a common link in these diseases is diminished mitochondrial oxidative phosphorylation and response to oxidative injury. Key regulators of mitochondrial function, the nuclear respiratory coactivators help to regulate mitochondrial oxidative phosphorylation and prevent cellular and neuronal injury. SIRT1 is a member of the sirtuin family of NAD+dependent deacetylases, which is proposed to be responsible for health benefits provided by caloric restriction. Furthermore, resveratrol found in the skin of red grapes increases the activity SIRT1, prolongs life-span in mice, and may prevent neurodegeneration. A key component of the protective response mediated by SIRT1 is deacetylation and activation of the transcription factor PGC-11 leading to increased mitochondrial regeneration and improved cellular oxidative energy metabolism. The role of SIRT1 and its mechanism/s of action at cellular level are uncertain;however investigators with a wide spectrum of research foci have an interest in understanding the biological actions of SIRT1 in different tissues. To study this, generation of transgenic mice that conditionally expresses SIRT1 is needed. In response to an PA from NCRR (PA-07-336) to develop animal models of human disease that are applicable to the research interests of two or more categorical NIH Institutes/Centers, we will develop a transgenic mouse that expresses mouse SIRT1 and mitochondrial targeted enhanced yellow fluorescent protein under the control of tetracycline responsive element (TRE-SIRT1/mito-eYFP). Co-expression of mito-eYFP with SIRT1 will be used to identify, isolate and study the influence of SIRT1 expression on mitochondrial function. Then, SIRT1 expression will be targeted to central and peripheral neurons by crossing it with CamKII-1 tTA mice. The transgenic mice developed in this study will aid investigators from NINDS, NIDDK, NIA and other institutes to test disease mechanisms and develop SIRT1 mediated therapies. Specifically in this proposal, we will investigate the mechanism by which SIRT1 protects central and peripheral neurons against diabetes-induced neuronal injury. The proposal also describes how the animal models produced can be developed by other investigators to study SIRT1 biology in non-neuronal cells. We have two aims: (1) To develop a transgenic mouse that expresses mouse SIRT1 under the control of tetracycline responsive element (TRE;TRE-SIRT1/mito-eYFP). (2) To phenotype the bigenic SIRT1 neuron specific mouse model. Lay description: Obesity, diabetes, and neurodegenerative diseases affect large numbers of people. The SIRT1 protein is considered to be a master regulator of the body's defense against disease and is activated by resveratrol found in red grapes.
We aim to uncover the mechanism by which S1RT1 protects neurons from diabetes induced neurological complications.
This proposal is submitted in response to a PA from NCRR PA-07-336 """"""""Development of Animal models and Related Biological Materials for Research"""""""". The research objective of this PA is to """"""""develop, characterize or improve animal models for human disease and that models to be considered must be applicable to the research interests of two or more categorical NIH Institutes/Centers"""""""". A major public health problem is the increase in the incidence of obesity-related diseases, such as diabetes and its complications and the increased incidence of neurodegenerative diseases, for example Parkinson's and Alzheimer's diseases in the aging population. We will develop a transgenic mouse that expresses mouse SIRT1 and mitochondrial targeted enhanced yellow fluorescent protein under the control of tetracycline responsive element (TRE-SIRT1/mito-eYFP). Co-expression of mito-eYFP with SIRT1 will be used to identify, isolate and study the influence of SIRT1 expression on mitochondrial function. Then, SIRT1 expression will be targeted to central and peripheral neurons by crossing it with CamKII-1 tTA mice. The transgenic mice developed in this study will aid investigators from NINDS, NIDDK, NIA and other institutes to test disease mechanisms and develop SIRT1 mediated therapies. Our overall hypothesis is that activation of SIRT1 in the central (CNS) and peripheral nervous system (PNS) would reduce oxidative stress and improve regulation of Mt function in neurons and other tissues that may be important in neurodegenerative diseases, diabetes and its complications, and in delaying or reducing the effect of aging in the nervous system. Activation of the sirtuins offers the potential for a novel treatment of several human diseases that are related to oxidative injury and defects of mitochondrial function.
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