Renee C. LeBoeuf - US grants
Affiliations: | University of Washington, Seattle, Seattle, WA |
Area:
Neuroscience Biology, Nutrition, PathologyWe are testing a new system for linking grants to scientists.
The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
You can help! If you notice any innacuracies, please sign in and mark grants as correct or incorrect matches.
High-probability grants
According to our matching algorithm, Renee C. LeBoeuf is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
---|---|---|---|---|
1988 — 1992 | Leboeuf, Renee C | R29Activity Code Description: Undocumented code - click on the grant title for more information. |
High Density Lipoproteins and Atheroschlerosis @ University of Washington The long-term goal of this research project is to define genetic and metabolic factors involved in the development of atherosclerosis. This disease is the leading cause of mortality in the Western world and its risk of onset appears to be influenced by nutritional and genetic factors. The hereditary component in atherosclerosis is likely to be complex and characterized by the involvement of a large number of genes, many of which participate in determining the levels and structures of plasma lipoproteins. The study described here will focus on genetic factors controlling high density lipoproteins (HDL) and the role of HDL in atherosclerosis. This interest stems from human epidemiological studies which show a strong association of high plasma concentrations of HDL with a reduced risk of heart disease. The mechanism of protection and why individual differences exist in plasma levels of HDL subclasses is not known. The mouse genetic system is used here to determine the genetic and physiological factors giving rise to these differences and to shed light on the manner in which HDL protect against heart disease. The mouse is the classical mammal for genetic studies because of the hundreds of inbred strains, detailed chromosome map, special genetic tools and unusual strains. In contrast, only limited aspects of the genetic regulation of lipoproteins can be examined directly in humans. Important complications in human studies are interactions between environment and genetic factors, and genetic heterogeneity among human populations which makes it difficult to study the effects of individual genes unless those effects are relatively gross. Polymorphisms have been identified among mouse strains using antibodies and cDNA clones to specific proteins involved in lipid transport (LCAT, lipases, transfer proteins, apolipoproteins, etc.). These polymorphisms will be used to investigate genetic and physiological factors giving rise to different HDL subpopulations. Further, a gene determining atherosclerosis susceptibility in mice, called Ath-1, will be characterized. Its action involves metabolic mechanisms related to changes in plasma HDL levels. The identity of Ath-1, in terms of its gene product, will be characterized. Its action involves metabolic mechanisms related to changes in plasma HDL levels. The identity of Ath-1, in terms of its gene product, will be determined using antibodies and cDNA clones specific for lipid transport proteins. Together, this information will shed light on basic factors controlling lipid transport and atherosclerosis. |
1 |
1993 — 1995 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dietary and Genetic Control of Hdl-Binding Protein-1 @ University of Washington Our long-term goal is to identify dietary and genetic factors regulating the expression of HDL binding protein-1 (HBP-1). This protein appears to be responsible for the active excretion of cholesterol from cells. We hypothesize that when cells become loaded with cholesterol in vivo via diet and/or genetic abnormalities, HBP-1 would serve to protect against atherogenesis through reverse cholesterol transport processes. This project has four specific aims which are to: (1) characterize the molecular and genetic factors involved in dietary regulation of HBP-1 expression; (2) characterize the gene for HBP-1; (3) generate transgenic mice overexpressing HBP-1; and (4) generate mice unable to express functional HBP-1 protein using gene targeting technology. The first aim will be accomplished by screening mouse strains for differences in structures and quantitative levels of HBP-1 protein and mRNA. The expression of HBP-1 has already been shown to be altered by cellular cholesterol content in cell culture studies. This aim will establish this behavior in vivo and determine modes of inheritance and regulation for HBP-1. In the second aim, mouse genomic clones will be obtained by conventional techniques using human cDNA already available. One purpose is to generate appropriate genomic clones for use in aim #4, and the other is to identify specific regulatory regions based on genomic sequences. In the third aim, mice overexpressing HBP-1 will be generated and used to determine whether overexpression will prevent or retard atherogenesis in diet-induced, atherosclerosis-susceptible mice of strain C57BL/6. Further, transgenic mice will be fed semi-synthetic diets designed to alter cellular cholesterol content for functional studies of HBP-1. The fourth aim uses homologous recombination technology to generate mice in which the HBP-1 gene is dysfunctional. We will determine whether the absence of functional HBP-1 will promote atherogenesis in otherwise resistant mice. The experimental procedures described in this proposal represent a comprehensive strategy to define the importance of HBP-1 in whole animal lipoprotein metabolism and its relevance to protection against atherosclerosis. Our eventual goal is to design specific dietary interventions to protect against atherosclerosis. |
1 |
1995 — 1999 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling Alzheimers Disease--by Amyloid and Apoe @ University of Washington DESCRIPTION: (adapted from Applicant's Abstract) AD is a devastating neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. The long-term goal of this research is to elucidate the role of beta-amyloid protein (Ab) and apolipoprotein (apo)E in the pathogenesis of Alzheimer's disease (AD). A possible role for Ab as either a marker for AD onset and progression or as a causative factor is supported by its marked accumulation in neuritic plaques and cerebrovascular sites. Genetic, epidemiological, and biochemical evidence is mounting that apoE exerts an isoform specific-effect on the rate or extent of development of AD. The investigators already demonstrated that overexpression of a C-terminal region of amyloid precursor protein (APP) leads to the production of Ab-bearing 14 and 15 kDa neurotoxic fragments in cultured neuronal cells. In addition, the investigators have already created transgenic mice that overproduce these 14 and 15 Kda fragments. These mice are said to produce more protein product in brain than reported by other investigators. Although they have not observed any obvious pathological changes in the brains of their transgenic mice (up to 26 months), amyloid deposits have been observed in the intestines of these mice. They hypothesize that other factors may be necessary for the induction of neuropathological changes associated with AD, such as expression of specific apoE alleles, or quantities of these alleles. Thus, the Specific Aims of this research proposal are to: (1) establish transgenic mice overexpressing human apoE3 and apoE4; (2) establish transgenic mice overexpressing Ab with different apoE genotypes; and (3) analyze transgenic mouse lines for AD symptoms. ApoE allele specific CDNA constructs will be made with a cytomegalovirus promoter system. Overexpression of human apoE (apoE3-e3 mice and apoE4-e4 mice) will be established in mice lacking endogenous apoE expression (apoE "knock-out" mice) by a combination of transgenic and breeding schemes. These mice will be studied and crossed to mice overexpressing Ab to determine the effects of each genetic change and gene interactions on the propensity of AD pathology. The development of animal models expressing various forms of apoE in the presence of marked amyloid expression may provide excellent tools in which to study the progression, prevention, and treatment of AD. |
1 |
1997 — 1999 | Leboeuf, Renee C | P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Modeling Alzheimer's Disease--B Amyloid and Apoe @ University of Washington AD is a devastating neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. The long-term goal of this research is to elucidate the role of B-amyloid protein (AB) and apolipoprotein E (apoE) in the pathogenesis of AD. A possible role for AB as either a marker for AD onset and progression or as a causative factor is supported by its marked accumulation in neuritic plaques and cerebrovascular sites. Genetic, epidemiological, and biochemical evidence is mounting that apoE exerts an isoform specific-effect on the rate or extent of development of AD. We have already demonstrated that over-expression of a C-terminal region of amyloid precursor protein (BPP) leads to the production of AB-bearing 14 and 15 kDa neurotoxic fragments in cultured neuronal cells. In addition, we have already created transgenic mice that overproduce these 14 and 15 kDa fragments. These mice produce more protein product in brain than reported by any other investigator. Although we have not observed any obvious pathological changes in the brains of our transgenic mice (up to 26 months), amyloid deposits have been observed in the intestines of these mice. We hypothesize that other factors may be necessary for the induction of neuropathological changes associated with AD, such as expression of specific apoE alleles, or quantities of these alleles. Thus, the specific aims of this research proposal are to: (1) establish transgenic mice over-expressing human apoE3 and apoE4; (2) establish transgenic mice over-expressing human AB with different apoE genotypes; and (3) analyze transgenic mouse lines for AD symptoms. ApoE allele specific cDNA constructs will be made with a cytomegalovirus promoter system. Over-expression of human apoE (apoE3-E3 mice and apoE4-E4 mice) will be established in mice lacking endogenous apoE expression (apoE "knock-out" mice) by a combination of transgenic and breeding schemes. These mice will be studied and crossed to mice over-expressing AB to determine the effects of each genetic change and gene interactions on the propensity of AD pathology. The development of animal models expressing various forms of apoE in the presence of marked amyloid expression may provide excellent tools in which to study the progression, prevention, and treatment of AD. |
1 |
1997 — 2001 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of Atherosclerosis in Diabetic Mice @ University of Washington DESCRIPTION (Adapted from Applicant's Abstract): The long term goal is to identify molecular mechanisms for the onset of accelerated atherosclerosis in diabetes mellitus. This will be accomplished by studying animal models susceptible to both diabetes and atherosclerosis. The investigators have now developed several mouse models which show accelerated atherosclerosis upon becoming diabetic. These include the BALB/c strain treated with streptozotocin and fed a high fat/cholesterol diet, and diabetic NOD mice. These and other mouse strains will be used to identify genetic and environmental factors influencing atherosclerosis due to the diabetic state, and to explore possible steps toward treatment or prevention of atherosclerosis disease in diabetics. There are four specific aims. The first aim is to characterize lesion cellular composition and vascular sites of development. Immunocytochemical and histological approaches will be used. The hypothesis is that diabetes induces differences in lesion composition and location in the vasculature. The second aim is to identify biochemical pathways through which hyperglycemia and dyslipidemia enhance oxidation at the artery wall and in model tissues using gas chromatography/mass spectroscopy and specific antibodies. The investigators hypothesize a role for oxidation in accelerated atherosclerosis. The third aim is to determine whether hyperglycemia and dyslipidemia alter the expression of inflammatory genes and matrix molecules at the artery wall and in model tissues. Gene expression will be studied at the level of mRNA and protein in artery wall and liver tissues. The fourth aim is to determine whether atherosclerosis can be ameliorated by treatment with insulin and/or dietary anti-oxidants. In summary, the investigators have created a panel of mouse models which can be compared and contrasted as to the mechanisms leading to atherosclerosis onset in the diabetic state. Studies will also be initiated toward identifying treatments to retard or reverse atherosclerosis in diabetics. |
1 |
2002 — 2005 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gene Regulation of Atherosclerosis in Diabetic Animals @ University of Washington [unreadable] DESCRIPTION (provided by applicant): Our long term goal is to identify molecular mechanisms for the onset of accelerated atherosclerosis in diabetes mellitus. This will be accomplished by studying animal models susceptible to both diabetes and atherosclerosis. During the previous grant period, we developed new mouse models, which show remarkable changes at the artery wall due to diabetes. BALB and BALB.LDLR-/- mice develop vascular lesions which are accelerted by hyperglycemia but are independent of changes in plasma lipids. In contrast, C57BL/6 and C57BL/6.LDLR-/- develop lesions which are not reflective of hyperglycemia. We use this genetic difference to test the hypothesis that hyperglycemia modulates the expression and/or function of specific genes causing diabetic macrovascular disease, in three aims: Aim 1: Identify major gene(s) determining the increased atherosclerosis in response to hyperglycemia. We use microarray technology coupled to mouse genetics for validation to identify such genes. Aim 2: Determine the role of specific candidate gene pathways in diabetic vascular disease. We study candidate proteins of perlecan, MMP-9 and MMP-13, and connexins 43 and 45 in our mouse system. Aim 3: Determine whether interventions aimed at reducing oxidative stress or protease activity can protect BALB from diabetic vascular disease. Anti-oxidant diets and diets containing synthetic protease ihibitors are used to test the general role of these pathways in diabetic vascular disease. Together, this information will provide potential gene targets for future prediction and treatment of diabetic macrovascular disease in humans |
1 |
2005 — 2008 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genes Modulating Diet-Induced Diabetes in Mice @ University of Washington DESCRIPTION (provided by applicant): Type 2 diabetes and obesity have become epidemics in our country and it is expected that 300 million people will develop type 2 diabetes within the next 25 years. For the vast majority of these individuals, causative genes and biochemical mechanisms leading to disease development remain unknown. Human linkage studies have been helpful for <2% of single genes causing forms of type 2 diabetes, but common cases are under multigenic control, and specific causative genes have not been identified. To accelerate the identification of genes predisposing to obesity and type 2 diabetes, mouse systems are proving useful. We make use of strains A/J and C57BL/6, which are resistant and susceptible, respectively, to diet-induced obesity and type 2 diabetes. We utilize unique and novel strains derived from A/J and C57BL/6 called chromosome substitution strains (CSSs), developed by Dr. Joseph Nadeau (Case Western Univ.). Each strain has one chromosome derived from A/J amongst the genetic background of C57BL/6. These strains allow rapid assignment of specific traits, such as body weight and plasma glucose levels, to specific chromosomes. They also facilitate the next steps of congenic mapping needed to eventually fine map and identify genes controlling obesity and diabetes in the face of high fat and sugar diets. We have three specific aims, which are to (1) Identify chromosomes harboring genes controlling obesity and diabetes, and (2) Construct congenic strains containing chromosomal intervals regulating obesity and diabetes, and (3) Develop crosses for fine structure mapping. Work toward the first aim is progressing well and we have already identified several chromosomes containing A/J alleles modulating body weight and plasma glucose levels. The second and third aims will involve breeding informative CSSs and recombinant inbred lines to C57BL/6 to capture smaller chromosomal regions of active A/J alleles. Overall, this proposal will move the field forward toward identifying genes controlling the complex disorders of obesity and type 2 diabetes. |
1 |
2006 — 2009 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vascular Disease and Inflammation in Mice @ University of Washington [unreadable] DESCRIPTION (provided by applicant): Inflammatory processes are characterized by tissue- targeted accumulations of lymphocytes and the local elaboration of adhesion molecules, growth factors, proteases and cytokines. These processes originate in response to infectious agents and tissue trauma. Diseases such as rheumatoid arthritis, atherosclerosis, pulmonary fibrosis and Crohn's disease are examples of deleterious inflammation. Understanding the pivotal relationships in cell biology which control protection versus chronic damage is critical for preventing disease and treating millions of individuals with such diseases. Here, we study atherosclerosis as a model for inflammation. [unreadable] [unreadable] The long range goal is to understand how tumor necrosis factor alpha (TNF) receptors and ligands, TNF and lymphotoxin (LTa) contribute to atherosclerosis. Although studies implicate TNF as playing a deleterious role in atherosclerosis, our data suggests that its contribution is more complicated and dependent upon stage of atherosclerosis and cell types involved. In addition, we are the first group to show that LTa is present at the artery wall and loss of LTa also influences the progression of atherosclerosis. We are using mice deficient and transgenic in TNF ligands or receptors to demonstrate how these molecules contribute to atherogenesis and atheroprogression in three specific aims: (1) determine the role of TNF in cholesterol homeostasis in macrophages, (2) determine whether pharmaceutical inhibition or induced gene expression of TNF or LTa results in improvement in atherosclerosis severity, (3) determine the relative contribution of TNF family members derived from the hematopoietic compartment versus the fixed tissue compartment in atherosclerosis. [unreadable] [unreadable] Overall, this work will provide new and detailed information about the relative contributions of TNF molecules to atherosclerosis. We believe that detailed knowledge is still needed in the TNF field to realize the important goal of developing therapies which harness anti-atherogenic functions of TNF. [unreadable] [unreadable] [unreadable] |
1 |
2006 — 2010 | Leboeuf, Renee C | U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
Mmpc: Diabetes and Diabectic Complications @ University of Washington DESCRIPTION, OVERALL (provided by applicant): The major goal of the Mouse Metabolic Phenotyping Center at the University of Washington is to promote and facilitate the study of animal models of obesity, diabetes and pathological complications due to these disorders. Because of the multidisciplinary nature of phenotyping approaches, close interaction across medical, pathological, and molecular disciplines is necessary to characterize animals used to study human diseases. By providing a number of Core facilities, the Seattle MMPC integrates and coordinates research activities so that Customers interested in having their animal models characterized can obtain a dear picture of the metabolic and disease state for each animal. The five Cores are: 1) an Administrative Core that is responsible for the day-to-day administration of the MMPC including the Pilot & Feasibility Program of the Animal Models of Diabetic Complications Consortium (AMDCC); 2) an Animal Core which will ensure proper delivery of animals and appropriate distribution to other Cores, and monitor health, husbandry and proper treatment of animals; 3) a Diabetes and Energy Balance Core to provide facilities for measuring body composition, energy expenditure, metabolic phenotyping and evaluation of type 1 and type 2 diabetes; 4) a Cardiovascular Core to provide assessment of heart function in normal and challenged states, vascular pathology quantifications, and response to injury modeling; 5) a Microvascular and Retinopathy Core which will evaluate kidney function and structural changes as well as extent of pathology in the eye. Four of the Core units are supported by HUBs which collect within each HUB, general technologies. Within the Animal Core is the Animal HUB which provides personnel to aid in dispersal of animals to the appropriate core facilities and to aid investigators in phenotyping. The Diabetes and Energy Balance Core harbors the Analytical HUB which is responsible for quantification of RNA, proteins, carbohydrates, and any other analyte needed in this MMPC. The Surgery HUB is within the Cardiovascular Core and provides surgery expertise for this Core and any surgery needs extending from other Cores. The Morphology HUB, located within the Microvascular/Retinopathy Core, is responsible for all tissue preparation and analysis. Thus, this MMPC provides outstanding facilities and support for the large and varied obesity and diabetes research base which includes our University, AMDCC investigators, and other potential Customers across the country. |
1 |
2008 — 2012 | Leboeuf, Renee C O'brien, Kevin Douglas [⬀] |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
@ University of Washington Animal Experiments; Area; Arterial Fatty Streak; Atheroma; Atheromatous; Atheromatous degeneration; Atheromatous plaque; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Body Tissues; Breeding; Cell/Tissue, Immunohistochemistry; Cells; Collection; Diabetic mouse; Effectiveness, Program; Experiments, Animal; Expertise, Technical; Fixation; Freezing; Genetics, in situ Hybridization; IHC; Immunofluorescence Microscopy; Immunohistochemistry; Immunohistochemistry Staining Method; In Situ Hybridization; Individual; Investigators; Longitudinal Studies; Maintenance; Maintenances; Mammals, Mice; Methods; Methods and Techniques; Methods, Other; Mice; Microscopy, Immunofluorescence; Modeling; Murine; Mus; Paraffin Embedding; Pathology; Process; Program Effectiveness; Programs (PT); Programs [Publication Type]; Research Personnel; Researchers; Staining method; Stainings; Stains; Streaks, Arterial Fatty; Technical Expertise; Techniques; Tissue Banks; Tissue Collection; Tissue/Specimen Collection; Tissues; atheromatosis; atherosclerosis plaque; atherosclerotic lesions; atherosclerotic plaque; atherosclerotic vascular disease; base; cost effectiveness; design; designing; in situ Hybridization Staining Method; long-term study; mouse model of diabetes; programs; sample fixation; vulnerable plaque |
1 |
2009 | Leboeuf, Renee C | U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
@ University of Washington DESCRIPTION, OVERALL (provided by applicant): The major goal of the Mouse Metabolic Phenotyping Center at the University of Washington is to promote and facilitate the study of animal models of obesity, diabetes and pathological complications due to these disorders. Because of the multidisciplinary nature of phenotyping approaches, close interaction across medical, pathological, and molecular disciplines is necessary to characterize animals used to study human diseases. By providing a number of Core facilities, the Seattle MMPC integrates and coordinates research activities so that Customers interested in having their animal models characterized can obtain a dear picture of the metabolic and disease state for each animal. The five Cores are: 1) an Administrative Core that is responsible for the day-to-day administration of the MMPC including the Pilot &Feasibility Program of the Animal Models of Diabetic Complications Consortium (AMDCC);2) an Animal Core which will ensure proper delivery of animals and appropriate distribution to other Cores, and monitor health, husbandry and proper treatment of animals;3) a Diabetes and Energy Balance Core to provide facilities for measuring body composition, energy expenditure, metabolic phenotyping and evaluation of type 1 and type 2 diabetes;4) a Cardiovascular Core to provide assessment of heart function in normal and challenged states, vascular pathology quantifications, and response to injury modeling;5) a Microvascular and Retinopathy Core which will evaluate kidney function and structural changes as well as extent of pathology in the eye. Four of the Core units are supported by HUBs which collect within each HUB, general technologies. Within the Animal Core is the Animal HUB which provides personnel to aid in dispersal of animals to the appropriate core facilities and to aid investigators in phenotyping. The Diabetes and Energy Balance Core harbors the Analytical HUB which is responsible for quantification of RNA, proteins, carbohydrates, and any other analyte needed in this MMPC. The Surgery HUB is within the Cardiovascular Core and provides surgery expertise for this Core and any surgery needs extending from other Cores. The Morphology HUB, located within the Microvascular/Retinopathy Core, is responsible for all tissue preparation and analysis. Thus, this MMPC provides outstanding facilities and support for the large and varied obesity and diabetes research base which includes our University, AMDCC investigators, and other potential Customers across the country. |
1 |
2010 — 2013 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Anti-Inflammatory, Cholesterol Export, and Cardioprotective Functions of Abca1 @ University of Washington Atherosclerotic cardiovascular disease (CVD) is the most common cause of mortality and morbidity in the Western world. Cholesterol accumulation in arterial macrophages and inflammation of the artery wall both contribute to development of CVD. There is an inverse relationship between plasma high-density (HDL) levels and cardiovascular risk, implying that factors associated with HDL metabolism are cardioprotective. HDL protects against CVD by several mechanisms that remove cholesterol from arterial cells and suppress inflammation. A major cardioprotective factor associated with HDL metabolism is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that exports cholesterol and phospholipids from cells to lipid-depleted HDL apolipoproteins, such as apoA-I. We found that ABCA1 also functions as an anti-inflammatory signaling receptor through activation of a JAK2/STAT3 pathway, which is independent of cholesterol export activity. Thus, macrophage ABCA1 provides a direct biochemical link between the cardioprotective effects of reverse cholesterol transport and suppressed inflammation. These observations indicate that ABCA1 is an attractive therapeutic target for treating the two major underlying mechanisms that cause CVD. The goal of this project is to determine the cellular processes involved in the cholesterol export and anti-inflammatory activities of ABCA1 and to assess their cardioprotective roles in vivo. We propose to use mutagenesis, biochemical, and mass spectrometric techniques to evaluate the effects of apolipoprotein-ABCA1 interactions on cholesterol export and inflammatory cytokine production and to characterize cellular mechanisms involved. We also propose to use atherosclerosis-susceptible mouse models to determine how these anti-inflammatory and cholesterol export functions of ABCA1 contribute to atherosclerosis in whole animals. This information will define possible sites of impairment of these pathways that may be clinically relevant and uncover potential targets for therapeutic interventions for preventing CVD. |
1 |
2010 — 2013 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Predisposition For Intimal Hyperplasia in Mice @ University of Washington DESCRIPTION (provided by applicant): Smooth muscle cell (SMC) accumulation and extracellular matrix deposition in the intima are major characteristics of neointimal hyperplasia (IH) which occurs frequently following all forms of vascular reconstruction, including stenting, angioplasty, endarterectomy and vein grafts. A common result of IH is the reduction of the vessel lumen diameter leading to important clinical problems such as angina, stroke, thrombosis and myocardial infarction. It is our goal to identify biomarkers to assess risk of developing IH and molecular mediators for the development of therapies to treat susceptible vessels. Among mouse strains, there is a wide range of responses to carotid artery injury as induced by ligature, slow flow or endothelial denudation ranging from mice that are completely resistant those which develop large neointimal lesions. Here, we exploit these phenotypic differences by using genetic linkage and association studies to identify genes modulating vascular pathology in carotid arteries. Since the last submission, we have altered the emphasis of our outstanding research team to include family linkage and association study expertise. We also nearly doubled an F2 population between FVB (susceptible) and C57BL/6 (resistant) strains and identified 6 quantitative trait loci (QTL). An identity by descent analysis was performed across 10 inbred strains to reduce QTL intervals which yielded 8 candidate genes worthy of further study. We also screened 9 inbred mouse strains in anticipation of entering them into a large association study. We present validation data for one candidate gene and show its relevance to the IH process. Overall, we expect to use this unbiased system for the discovery of novel genes controlling IH. Work will be conducted as described in three Specific Aims: (1) Identify chromosomal intervals containing genes modulating susceptibility and resistance to injury-induced neointimal hyperplasia (IH). We will use classic linkage studies to identify QTL and haplotype analysis across F2 mice to eliminate regions that are shared identical by descent. (2) Identify genes and molecular pathways mediating responsiveness to carotid artery injury using genome wide association studies. We will use a mouse diversity panel of ~100 inbred strains for which genotypes are already known and obtain IH phenotypes for association studies. (3) Validate and determine functions for potential candidate genes controlling IH. Candidate genes discovered in Aims 1 and 2 will be studied further here. Such studies will include identification of cell type(s) involved in expression, characterization of molecular functions in cultured cells, and development of appropriate genetically engineered mice. Overall, the strengths of this proposal include: (a) the novelty of the topic; (b) outstanding research team; (c) currently existing QTL for IH; and (d) strong preliminary data identifying a candidate gene with potential IH-modulating activity which demonstrates the utility of our approach. Further, the health topic is of high significance as tens of thousands of individuals are affected by vascular injury each year. |
1 |
2012 | Leboeuf, Renee C | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role For S1p2 in the Arterial Injury Response @ University of Washington Project Summary: Intimal hyperplasia is caused by proliferation and migration of intimal smooth muscle cells (SMCs) and contributes to restenosis (the re-occlusion of vessels) after arterial reconstruction. This proposal investigates the possibility that intimal growth occurs because a pathway that normally inhibits excessive proliferation of SMCs after injury is suppressed. We have found that carotid injury in a mouse lacking the type-2 receptor for sphingosine-1-phosphate (S1P2), but not in their wild-type counterpart, results in the formation of a large neointima. Because S1P2-deficient mice develop normally and do not exhibit any vascular phenotype, S1P2 does apparently not play a critical role in the development of the vasculature. Our overall hypothesis is that S1P is generated after injury and binds to S1P2, which causes activation of serum-response factor and its cofactor of the myocardin-like protein family. This transcription factor complex is known to regulate expression of SMC-specific genes, and we hypothesize that these genes inhibit SMC proliferation. This inhibitory pathway is absent in the S1P2 knock-out mouse, and this might be the reason that these animals develop large intimal lesions in response to arterial injury. The goal of this proposal is to test this hypothesis, and four specific aims are proposed. In aim 1, we will measure expression of SMC- specific genes in injured arteries of wild-type and S1P-deficient mice. In aim 2, we will define a role for all three S1P receptors expressed in SMCs in the regulation of SRF- dependent genes. In aim 3, we will characterize the transcriptional complex that is activated by S1P2 and regulates the expression of SMC-specific genes. In aim 4, we will use micro array technology to identify novel genes in the vessel wall that are directly controlled by S1P2 in response to injury. Relevance to public health: Restenosis is a serious and costly complication of arterial repair which occurs in ca. 30% of patients. Variations in S1P2 expression levels and signaling might determine if intimal lesions develop. Thus, proteins in the S1P2 pathway may constitute promising novel targets to pharmacological control of intimal growth. Relevance to public health: Restenosis is a serious and costly complication of arterial repair which occurs in ca. 30% of patients. Variations in S1P2 expression levels and signaling might determine if intimal lesions develop. Thus, proteins in the S1P2 pathway may constitute promising novel targets to pharmacological control of intimal growth. |
1 |