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Targeting an atypical signaling hub to restore and protect whole body glucose homeostasis

针对非典型信号中枢恢复和保护全身葡萄糖稳态

基本信息

批准号：
10311546
负责人：
Debbie C Thurmond
金额：
$ 44万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-12 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311546
关键词：
Acute Apoptosis Beta Cell Blood Circulation Blood Glucose Cell model Cell physiology Cell surface Cells Cities Data Defect Development Diabetes Mellitus Diet Disease Environment Epidemic Event Exposure to F-Actin Failure Fasting Fatty acid glycerol esters Functional disorder Funding GLUT 4 protein Glucose Glucose Intolerance Goals Health Human Hyperglycemia Insulin Insulin Resistance Intake Intervention Knock-out Knockout Mice Knowledge Link Mechanics Mediating Mission Mitochondria Molecular Mus Muscle Fibers Myocardial Infarction National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Outcome Pathway interactions Peripheral Persons Population Prediabetes syndrome Predisposition Prevention Process Protein Kinase Proteins Public Health Research Research Proposals Role Sampling Secretory Cell Signal Pathway Signal Transduction Skeletal Muscle Stimulus Stress Stroke Structure Structure of beta Cell of islet Testing Therapeutic Tissues Translations Vesicle Work base blood glucose regulation cardiovascular risk factor cell type diabetogenic glucose uptake human tissue impaired glucose tolerance improved in vivo innovation insulin granule insulin secretion insulin sensitivity islet knock-down mitochondrial dysfunction mortality mouse model new therapeutic target novel p21 activated kinase prevent therapeutic target tool

项目摘要

Project Summary/Abstract – Type 2 diabetes (T2D) has now reached epidemic proportions worldwide. During pre-diabetes, blood sugars rise and the risk of cardiovascular consequences, such as stroke, myocardial infarction and mortality, is already increasing by 2-4-fold. Despite this, there remains a fundamental gap in understanding how and why pre-diabetes develops. Strategies to halt or reverse T2D development require a multi-pronged approach, since the pathophysiology involves both dysfunction in pancreatic β-cell glucose- stimulated insulin release, and in skeletal muscle (skm) glucose uptake/clearance from the circulation. Factors linked to failures in both processes are considered optimal therapeutic targets. We have identified the p21- activated kinase, PAK1, as such a factor; it is a signaling hub in both the β-cells and skm that orchestrates multiple aspects of glucose homeostasis. PAK1 is deficient in T2D, suggesting that its loss may be a “roadblock” that prevents normal signaling in T2D. To overcome the roadblock of PAK1 deficiency, we need to understand the mechanisms linking PAK1 to its functions in β-cells and skm. Our long-term goal is to understand how β-cell and skm signaling can be manipulated to prevent or reverse pre-diabetes and halt the progression to T2D. Our central hypothesis is that 1) signaling through the PAK1 hub in the β-cell controls functional β-cell mass to reverse HFD-induced glucose intolerance, and that 2) PAK1 signals in skm confer protection from insulin resistance and engage in tissue crosstalk to enhance β-cell function. The rationale for the proposed research is that once these new mechanisms of the PAK1 effectors are elucidated, select signaling pathways from the PAK1 hub can be manipulated to prevent or reverse T2D. During the last funding cycle, we revealed that restoring PAK1 in T2D human islet β-cells reverses dysfunctional insulin secretion while reducing β-cell mitochondrial dysfunction and apoptosis. We also showed that PAK1 enrichment in skm protects against HFD-induced glucose intolerance, and engages in tissue crosstalk to improve β-cell function. Our provocative new preliminary data also indicate which PAK1 effectors carry out these essential functions. Therefore, the objective of this application is to test these candidate mechanisms linking PAK1 effector enrichment and protection of β-cells and skm from diabetogenic stress and to evaluate candidate PAK1 effector enrichment therapeutics. We will use our inducible tissue-specific mouse models and human tissues/cells for these studies. In Aim 1, we will identify how the PAK1 effectors restore β-cell function; in Aim 2, we will elucidate the mechanism(s) by which PAK1-effectors protect β-cell mass; in Aim 3, we will discern the mechanisms by which skm PAK1 contributes to peripheral insulin sensitivity and β-cell health. We will use innovative molecular tools to test novel hypotheses about these PAK1 effector actions in the context of a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a promising candidate strategy to reverse pre-diabetes and halt progression to T2D and by uncovering novel mechanisms of glucose homeostasis.

项目摘要/摘要- 2型糖尿病（T2D）现已在全球范围内达到流行病的程度。在