Apolipoprotein Genes and Atherogenesis in Animals

动物载脂蛋白基因和动脉粥样硬化形成

• 批准号: 9189641
• 负责人: NOBUYO MAEDA
• 金额: $ 57.07万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189641
• 关键词: 129 Mouse; Affect; Animals; Aorta; Apolipoprotein E; Apolipoproteins; Area; Arteries; Atherosclerosis; Attention; Backcrossings; Blood Vessels; Blood flow; Branchial arch structure; Candidate Disease Gene; Cardiovascular Diseases; Chromosomes; Chromosomes, Human, Pair 1; Code; Complement; Complex; Congenic Strain; Deposition; Development; Developmental Process; Disease; Dyslipidemias; Family; GLI2 gene; Genes; Genetic; Genetic Crosses; Genetic Crossing Over; Genetic Determinism; Genome; Geometry; Gli2 protein; Goals; Grant; Growth; Heterogeneity; Homing; Human; Inbred Strain; Induced Mutation; Lesion; Life; Location; Maps; Mediating; Meiosis; Mus; Myocardial Infarction; Partner in relationship; Patients; Phenotype; Phosphorylation; Plant Roots; Population; Predisposition; Process; Quantitative Trait Loci; Race; Recombinants; Research; Risk; Risk Factors; SHH gene; Site; Stroke; Susceptibility Gene; Testing; Transgenes; Variant; Yeasts; Zinc Fingers; aortic arch; atherogenesis; clinically relevant; congenic; endodeoxyribonuclease SceI; endonuclease; genome wide association study; hemodynamics; male; mouse genome; novel strategies; nuclease; prevent; promoter; public health relevance; smoothened signaling pathway; tool; transcription factor

DESCRIPTION (provided by applicant): The overall goal of our research is to develop a deeper understanding of the genetic factors underlying dyslipidemia and atherosclerosis. Areas of complex blood flow develop plaques preferentially, and the influence of hemodynamics on plaque development has been discussed extensively. Evidence is also accumulating that atherosclerosis at different vascular locations can involve distinguishable risk factors, although little attention has been paid to genetic factors that influence the sites of plaque development. We have found that Apoe-/- mice with the 129S6 genetic background (129-apoE) are slower to develop plaques at the aortic root than are Apoe-/- mice with a C57BL/6J background (B6-apoE), yet the 129-apoE mice develop plaques more rapidly in the aortic arch. Our quantitative trait loci (QTL) mapping of an F2 population of Apoe-/- mice between these strains has identified two QTL peaks, Aa1 and Aa2 on chromosome 1, that influence the susceptibility of the aortic arch to develop lesions. QTL-Aa1 overlaps QTL-Ga1, a QTL that influences the geometry of aortic arch curvature. The aortic arch QTLs are distinct from those affecting aortic root lesions. These observations support our hypothesis that subtle differences in vessel formation during development influence the occurrence of atherosclerosis later in life. Specific Aim 1 will further refine the QTL-Aa1 and Aa2 maps using genetic crosses, congenics and genome comparisons of inbred strains, 129S6, C57BL6/J, DBA/2J, A/J and AKR. Specific Aim 2 will facilitate "targeted crossover" within QTL intervals. Identifying the genes that form a QTL is facilitated when a congenic region is subdivided by crossover during backcrossing. To accelerate this process, we will combine meiosis-specific expression of I-SceI, a homing endonuclease of yeast, with its recognition sequence inserted into candidate genes within the QTL regions. The atherogenic effects of the induced mutations and of the narrowed QTL intervals will be assessed on an apoE-null background. Specific Aim 3 will test whether variations in the Gli2 gene influence aortic arch geometry and atherosclerosis. Gli2 lies within the interval covered by our overlapping QTLs, Aa1 and Ga1, and it codes for a transcriptional factor that mediates the sonic hedgehog signaling important for many developmental processes, including remodeling of branchial arch blood vessels to form the aortic arch. Deciphering genetic factors that affect plaque initiation and growth at one location along the aorta but not at another location has direct clinical relevance. Gaining a better understanding of location-dependent plaque development is an important contribution to the long-term goal of preventing the disease or of treating it before it becomes life threatening.

描述（由申请人提供）：我们研究的总体目标是更深入地了解血脂异常和动脉粥样硬化的遗传因素。复杂血流区域优先发展斑块，血流动力学对斑块发展的影响已被广泛讨论。尽管很少有人关注影响斑块形成部位的遗传因素，但也有越来越多的证据表明，不同血管部位的动脉粥样硬化可能涉及可区分的风险因素。我们已经发现具有129 S6遗传背景的Apoe-/-小鼠（129-apoE）在主动脉根部形成斑块的速度慢于具有C57 BL/6 J背景的ApoE-/-小鼠（B6-apoE），然而，129-apoE小鼠在主动脉弓中更快地发展斑块。这些品系之间的小鼠已经鉴定出两个QTL峰，1号染色体上的Aa 1和Aa 2，其影响主动脉弓发展病变的易感性。QTL-Aa 1与QTL-Ga 1重叠，QTL-Ga 1是一个影响主动脉弓曲率几何形状的QTL。主动脉弓QTL与影响主动脉根部病变的QTL不同。这些观察结果支持了我们的假设，即发育过程中血管形成的细微差异会影响以后生活中动脉粥样硬化的发生。具体目标1将利用自交系129 S6、C57 BL 6/J、DBA/2 J、A/J和AKR的遗传杂交、同源性和基因组比较进一步完善QTL-Aa 1和Aa 2图谱。具体目标2将促进QTL区间内的“靶向交叉”。当在回交过程中通过交换细分同源区域时，有利于鉴定形成QTL的基因。为了加速这一过程，我们将结合联合收割机减数分裂特异性表达的I-SceI，酵母归巢核酸内切酶，其识别序列插入到QTL区域内的候选基因。将在apoE无效背景下评估诱导突变和缩小QTL间隔的致动脉粥样硬化效应。具体目标3将测试Gli 2基因的变异是否影响主动脉弓几何形状和动脉粥样硬化。Gli 2位于我们的重叠QTL，Aa 1和Ga 1所覆盖的区间内，它编码一种转录因子，该因子介导对许多发育过程至关重要的音刺猬信号传导，包括鳃弓血管重塑形成主动脉弓。破译影响主动脉沿着一个位置而不是另一个位置的斑块起始和生长的遗传因子具有直接的临床意义。更好地了解位置依赖性斑块的发展是预防疾病或在其危及生命之前治疗疾病的长期目标的重要贡献。

项目成果

Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo.

脂肪组织ATP结合盒转运蛋白A1在体内有助于高密度脂蛋白生物发生。

• DOI: 10.1161/circulationaha.111.025445
• 发表时间: 2011-10-11
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Chung S;Sawyer JK;Gebre AK;Maeda N;Parks JS
• 通讯作者: Parks JS

Pparg-P465L mutation worsens hyperglycemia in Ins2-Akita female mice via adipose-specific insulin resistance and storage dysfunction.

• DOI: 10.2337/db10-0673
• 发表时间: 2010-11
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Pendse AA;Johnson LA;Tsai YS;Maeda N
• 通讯作者: Maeda N

α-Lipoic acid protects diabetic apolipoprotein E-deficient mice from nephropathy.

• DOI: 10.1016/j.jdiacomp.2010.07.004
• 发表时间: 2011-05
• 期刊: Journal of diabetes and its complications
• 影响因子: 3
• 作者: Yi X;Nickeleit V;James LR;Maeda N
• 通讯作者: Maeda N

Correction to: Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice.

• DOI: 10.1186/s13024-017-0223-7
• 发表时间: 2017-11-03
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Engstrom AK;Snyder JM;Maeda N;Xia Z
• 通讯作者: Xia Z

Harmful effects of increased LDLR expression in mice with human APOE*4 but not APOE*3.

携带人类 APOE*4 但不携带 APOE*3 的小鼠中 LDLR 表达增加的有害影响。

• DOI: 10.1161/01.atv.0000094963.07902.fb
• 发表时间: 2004
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Malloy,SudiI;Altenburg,MichaelK;Knouff,Christopher;Lanningham-Foster,Lorraine;Parks,JohnS;Maeda,Nobuyo
• 通讯作者: Maeda,Nobuyo