Targeting the Pial Collateral Circulation for Mitigation of Cerebral Ischemia

针对软脑膜侧支循环缓解脑缺血

• 批准号: 8662826
• 负责人: JAMES E FABER
• 金额: $ 44.17万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662826
• 关键词: Adult; Aging; Alleles; Attention; Biology; Blood Circulation; Brain; Bypass; C57BL/6 Mouse; Caliber; Cerebral Ischemia; Cerebrum; Chromatin; Chromosomes, Human, Pair 7; Clinical; Clinical Treatment; Collateral Circulation; Congenic Strain; Coronary; DNA; Dental crowns; Development; Disease; Disease model; Embryo; Etiology; Evaluation; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genome; Grant; Heart; Human; Image; Inbred BALB C Mice; Inbred Strains Mice; Individual; Infarction; Injury; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Leg; Lower Extremity; Lytic; Maps; Mediating; Modeling; Molecular Profiling; Morbidity - disease rate; Mouse Strains; Mus; Myocardial Infarction; Obstruction; Outcome; Pathway interactions; Patients; Perfusion; Peripheral arterial disease; Phenotype; Physiological; Population; Regulatory Element; Reporting; Research; Research Personnel; Risk; Risk Assessment; Role; Severities; Signal Transduction; Signaling Pathway Gene; Site; Skeletal Muscle; Stream; Stroke; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Trees; Variant; Vascular Diseases; Work; acute stroke; artery occlusion; base; cardiovascular risk factor; cerebral artery; cerebrovascular; congenic; functional outcomes; genetic variant; in vivo; interest; knock-down; mortality; neuroimaging; outcome forecast; public health relevance; research study; risk variant; transcriptome sequencing; vector

DESCRIPTION (provided by applicant): Occlusive vascular disease of the brain, heart and lower extremities is the primary cause of morbidity and mortality in the US. Native (pre-existing) collaterals interconnect adjacent arterial trees and function as critical bypass vessels if obstruction occurs in one of the trees. Attention over the past 25 years has been on mechanisms mediating outward remodeling of collaterals in ischemic disease. However, until our work over the last three years, nothing was known about what controls the number and diameter (extent) of these vessels. We have shown that collateral extent in murine brain and other tissues varies widely due to genetic polymorphisms, resulting in a greatly increased risk-severity for ischemic injury of brain and other tissues in individuals having low collateral extenta finding recently confirmed in humans. We have discovered the major genetic locus, Candq1, responsible for most (70%) of this variation. We now seek to identify the polymorphic gene underlying this locus and its downstream effector pathway that regulate collateral formation. Aim I will fine-map Candq1 in a congenic strain-set that we have partly completed generating in preliminary studies: We will introgress informative partitions of the Candq1 locus of the C57BL/6 "high-collateral" strain into the BALB/c strain that has few-to-no collaterals in brain and other tissues. These congenic lines will then be phenotyped for collateral extent in brain and skeletal muscle, followed by functional analysis in a model of ischemic stroke in the positive congenic line(s) (+CNG) that most tightly partitions the causative region of Candq1. Aim II-A will additionally narrow the candidates by determining gene expression in the +CNG using RNA-Seq across Candq1, and also across the whole genome to identify potential downstream effectors. Aim II-B will further refine the candidates and targets, plus determine if a variant in cis/trans regulatory element underlies Candq1, using whole-genome chromatin mapping for active DNA regulatory sites. Aim I and II will thus identify the highest priority candidates that Am III will test for causality using in vivo gene targeting, cellular analyses, and functional outcomein stroke. This project will identify the primary driver gene that controls formation of the native collateral circulation and is responsible for its wide variation. Defining the gene underlying Candq1, and its downstream signaling effectors, will also pinpoint targets to develop as therapies aimed at inducing new collaterals to form in adults with few and/or who are at risk for or have suffered acute stroke or other cerebral ischemic conditions and diseases. Identifying this major allele that when polymorphic impairs collateral formation may also provide a genetic marker for use in these same patient groups.

描述（由申请方提供）：脑、心脏和下肢的闭塞性血管疾病是美国发病率和死亡率的主要原因。原生（预先存在的）侧枝连接相邻的动脉树，如果其中一棵树发生阻塞，则作为关键的旁路血管发挥作用。在过去的25年里，人们一直关注缺血性疾病中侧支血管向外重塑的介导机制。然而，直到我们过去三年的工作，我们还不知道是什么控制着这些血管的数量和直径（范围）。我们已经表明，小鼠脑和其他组织中的侧支程度由于遗传多态性而变化很大，导致最近在人类中证实的低侧支程度个体的脑和其他组织缺血性损伤的风险严重性大大增加。我们已经发现了主要的遗传位点Candq 1，负责大多数（70%）的这种变化。我们现在试图确定多态性基因的基础上，这个位点和其下游效应途径，调节侧枝形成。目的我将在我们已在初步研究中部分完成生成的同类菌株集中对Candq 1进行精细定位：我们将C57 BL/6“高侧支”菌株的Candq 1基因座的信息分区渗入到具有少量或无侧支的BALB/c菌株中。在大脑和其他组织中没有侧支。然后对这些同源系进行脑和骨骼肌侧支程度的表型分析，然后在缺血性卒中模型中对最紧密地划分Candq 1致病区域的阳性同源系（+CNG）进行功能分析。目的II-A将通过使用RNA-Seq跨Candq 1以及跨整个基因组确定+CNG中的基因表达来进一步缩小候选者范围，以识别潜在的下游效应物。目的II-B将进一步完善候选人和靶标，并使用全基因组染色质图谱确定Candq 1的顺式/反式调控元件中的变体是否是活性DNA调控位点的基础。因此，目标I和II将确定最高优先级的候选人，Am III将使用体内基因靶向，细胞分析和功能结局来测试中风的因果关系。该项目将确定控制天然侧支循环形成并导致其广泛变异的主要驱动基因。确定Candq 1及其下游信号效应子的基因，也将确定开发的目标，作为旨在诱导新的侧枝形成的治疗方法，这些侧枝形成于患有很少和/或患有急性中风或其他脑缺血性疾病和疾病的成年人。鉴定这种当多态性损害侧枝形成时的主要等位基因也可以提供用于这些相同患者组的遗传标记。