Lyons, Timothy J., MD
Lipoproteins and pedf and the vascular complications of diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes, Complications\Nephropathy, Epidemiology
Type of Grant: Clinical Translational Research
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Diabetic vascular complications (retinopathy, nephropathy, neuropathy, accelerated atherosclerosis) are devastating, reducing quality of life and life expectancy, and imposing an immense economic burden. Risks and mechanisms are still not adequately understood: conventional risks (elevated glucose, cholesterol, blood pressure) are only part of the explanation. New evidence implicates proteins that modulate the growth of new blood vessels. One such protein, 'Pigment Epithelium Derived Factor' (PEDF), inhibits blood vessel growth: in diabetes, levels tend to be low in the eye and kidney, but elevated in the liver and the blood-stream. Manipulating levels of PEDF holds promise for new therapies, but much greater understanding of its functions in various tissues is needed. PEDF activates a transcription factor ('PPAR-alpha') in cell nuclei that controls the function of many genes. A drug called fenofibrate, in long-standing use to lower blood triglycerides (fats contained in circulating VLDL), also activates PPAR-alpha, and has recently shown surprising and previously unknown beneficial effects on diabetic eye and kidney disease.
Our prospective project aims to elucidate the interactions between PEDF, VLDL, PPAR-alpha, and the vascular complications of diabetes. It utilizes serum samples from two of the world's most important prospective diabetes cohorts, the DCCT/EDIC (Type 1 diabetes) and the VA Diabetes Trial (Type 2) (we have long-standing collaborations with both), and for tissue studies, we will evaluate relevant metabolic pathways in post-mortem samples from people with and without diabetes and its complications. Our goal is to create the basis for new treatments to block the complications of diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project addresses mechanisms underlying the vascular complications of diabetes, which are major causes of morbidity and premature mortality world-wide. We will study a specific protein called ‘Pigment Epithelium Derived Factor (PEDF)’. PEDF is of interest because it has properties that are relevant and important to the health of blood vessels. These effects may be modulated by levels of certain lipoproteins (particles that transport fats in plasma), especially triglyceride-rich particles such as Very Low Density Lipoproteins (VLDL). We have proposed that PEDF alters gene expression (acting via a transcription factor called PPARa), affecting expression of the ‘VLDL receptor’ (VLDLR) (a protein expressed on cell membranes that recognizes VLDL). In turn, the VLDLR can affect cell signaling pathways, leading to cell proliferation or cell death. These effects may be modulated by interactions between VLDL and VLDLR, and may differ between tissues, and between small blood vessels (capillaries in the eye or kidney) and large blood vessels (arteries). Our proposal builds on long-standing work with two of the world’s best-characterized long-term diabetes study cohorts: the (Type 1) Diabetes Control and Complications Trial (DCCT) and its observational extension, Epidemiology of Diabetes Intervention and Complications (EDIC) and the (Type 2) Veterans Affairs Diabetes Trial (VADT). We will relate repeated measures of PEDF and VLDL to clinical events in the cohorts. In complementary studies, human diabetic and non-diabetic tissues from the National Disease Research Interchange (NDRI) will evaluate PEDF and related lipoprotein pathways.
The project will lead to new understanding of fundamental mechanisms, both injurious and protective, that determine the extent of vascular damage in diabetes. It will point the way to rational development of treatments for specific types of vascular injury. Such treatments might be delivered systemically, or in the case of retinopathy, locally, if tissue-specific effects are needed.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The primary cause of premature death in people with diabetes, and also considerable illness and disability, is the greatly increased prevalence of cardiovascular disease. Kidney disease associated with diabetes is the single most common cause of kidney failure, and eye disease (retinopathy), the most common cause of new onset blindness in working-age adults. This project seeks to discover previously unknown mechanisms for the development of heart attacks, strokes, poor circulation in the lower limbs, nephropathy, and retinopathy in people with Types 1 and 2 diabetes. It may also lead to new ways to identify people at the highest risk of developing these problems, and potentially, underpin the development of new preventive treatments. Specifically, if we can pinpoint the mechanisms that drive vascular injury, we may eventually be able to interrupt the disease process and prolong healthy life.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been involved in diabetes research for 30 years. The study of diabetes is rewarding and important because diabetes is so common and has such serious consequences, and also because it involves every system of the human body and relates to other important research areas including cardiovascular disease, ophthalmology, renal disease, and aging. This award will enable us to make an important contribution because it allows us to capitalize on existing resources taking advantage of important opportunities that otherwise might be lost. We can now perform sophisticated analyses on samples collected from about 1,000 Type 1 diabetic subjects from the DCCT, and about 1,000 Type 2 diabetic subjects who participated in the Veterans Administration Diabetes Trial, and relate these to clinical outcomes that have developed over a five year period. The work therefore will bring added value to a major national study, and will help our overall goal of improving our understanding of the vascular complications of diabetes.
In what direction do you see the future of diabetes research going?
Within my own area of interest, the mechanisms responsible for the development of complications, there is intense interest in understanding the cellular processes that underlie injury to blood vessels. New knowledge will identify the local environmental changes that take place in the walls of blood vessels, and how they affect signaling processes inside cells so as to promote disease. This knowledge will bring the opportunity to develop new treatments and to assess the efficacy and mode of action of existing treatments. Research will also address patient characteristics, including genetic attributes, which determine susceptibility to disease, and that will lead to new and perhaps personalized treatments to mitigate risk factors. Very likely, tissue-specific treatments to protect blood vessels in the eyes, kidneys, or coronary circulation will be developed. The knowledge will contribute to the broader body of knowledge about vascular disease in general, since there are close relationships between risk factors such as diabetes, pre-diabetes, dyslipidemia, inflammation, and hypertension.
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