Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

信号畸变和脑海绵状血管瘤发病机制

• 批准号: 10621246
• 负责人: Douglas A. Marchuk
• 金额: $ 129.54万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621246
• 关键词: ADAMTS; Acute; Affect; American; Animals; Anticoagulants; Blood; Blood Vessels; Blood capillaries; Brain; Cell Lineage; Cells; Chronic; Clinical Trials; Collection; Communities; Complex; Cytoprotection; Data; Development; Disease; Endothelial Cells; Endothelium; Environment; Event; Exhibits; Genes; Genetic Engineering; Genomics; Genotype; Goals; Growth; Hemorrhage; Histology; Human; Investigation; Laboratories; Lesion; Lesion by Stage; Modeling; Molecular; Molecular Probes; Molecular Profiling; Mus; Mutate; Mutation; Neurologic; Operative Surgical Procedures; PIK3CG gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Poison; Preparation; Process; Protein C; Role; Seizures; Signal Pathway; Signal Transduction; Somatic Mutation; Specimen; Stroke; TLR4 gene; Testing; Therapeutic Studies; Thrombomodulin; Tissues; Work; X-Ray Computed Tomography; activated protein C receptor; autosome; cell behavior; cerebral cavernous malformations; clinically significant; design; drug testing; follow-up; gain of function; genomic locus; gut microbiome; insight; lifetime risk; molecular marker; mouse model; mutant; new therapeutic target; novel; novel marker; overexpression; pharmacologic; pre-clinical; programs; recruit; stroke risk; success; therapeutic target; tool; transcriptomics; versican

Signaling Aberrations and Cerebral Cavernous Malformations Pathogenesis. In the first cycle of this program project our collaborative group has made significant discoveries concerning CCM pathogenesis. In this renewal we will follow up these discoveries towards a scientifically based therapy. Recent data from multiple laboratories in our program converge on a model in which somatically mutated, CCM-deficient endothelial cells poison the peri-lesional environment to recruit non-deficient cells into the growing lesion. We will investigate the molecular and cellular basis for this non-cell autonomous pathological mechanism, including single-cell genomic and transcriptomic analyses in mouse and human lesions and mechanistic studies in mouse models. We have also discovered that endothelial cells within murine and human CCMs express markedly increased levels of thrombomodulin and endothelial protein C receptor which leads to activation of endogenous anti-coagulant protein C. This discovery provides a new target for lesional hemorrhage, the most clinically significant phenotype associated with CCM. Importantly, to enable these and other studies we have generated new, more robust CCM mouse models that exhibit both rapid lesion growth and lesional hemorrhage. We have also identified an unexpected and novel signaling aberration involved in CCM growth – activation of PI3 kinase – a target with existing drugs and with others under development. We will investigate the role of PI3 kinase in CCM lesion growth and its inhibition as a potential therapy. In parallel, we will search for somatic mutations in other genes that might enable repurposing of other existing drugs for CCM therapy. By capitalizing on our successes over the past four years, our renewal is designed to move from discovery, to mechanism, and then on to investigation of therapies for CCM disease.

信号畸变和脑海绵状血管畸形发病机制。在该项目的第一个周期中，我们的合作小组在 CCM 发病机制方面取得了重大发现。在本次更新中，我们将跟进这些发现，以寻求基于科学的治疗方法。我们项目中多个实验室的最新数据集中在一个模型上，其中体细胞突变、CCM 缺陷的内皮细胞毒害病灶周围环境，将非缺陷细胞招募到不断生长的病灶中。我们将研究这种非细胞自主病理机制的分子和细胞基础，包括小鼠和人类病变的单细胞基因组和转录组分析以及小鼠模型的机制研究。我们还发现，小鼠和人类 CCM 内的内皮细胞表达的血栓调节蛋白和内皮蛋白 C 受体水平显着升高，从而导致内源性抗凝蛋白 C 的激活。这一发现为病变出血（与 CCM 相关的临床上最重要的表型）提供了新的靶点。重要的是，为了实现这些和其他研究，我们生成了新的、更稳健的 CCM 小鼠模型，该模型表现出快速的病变生长和病变出血。我们还发现了与 CCM 生长有关的一种意想不到的新颖信号异常——PI3 激酶的激活——这是现有药物和其他正在开发的药物的靶点。我们将研究 PI3 激酶在 CCM 病变生长中的作用及其作为潜在疗法的抑制作用。与此同时，我们将寻找其他基因的体细胞突变，这些突变可能使其他现有药物重新用于 CCM 治疗。通过利用过去四年的成功，我们的更新旨在从发现转向机制，然后研究 CCM 疾病的治疗方法。

项目成果

B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models.

• DOI: 10.1007/s11481-016-9670-0
• 发表时间: 2016-06
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Shi C;Shenkar R;Zeineddine HA;Girard R;Fam MD;Austin C;Moore T;Lightle R;Zhang L;Wu M;Cao Y;Gunel M;Louvi A;Rorrer A;Gallione C;Marchuk DA;Awad IA
• 通讯作者: Awad IA

Why Don't Cerebral Cavernous Malformations Go With the Flow?

脑海绵状血管瘤为何不随波逐流？

• DOI: 10.1161/circresaha.119.315984
• 发表时间: 2019
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Tang,AlanT;Kahn,MarkL
• 通讯作者: Kahn,MarkL

The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression.

• DOI: 10.1016/j.devcel.2014.12.009
• 发表时间: 2015-01-26
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Zhou Z;Rawnsley DR;Goddard LM;Pan W;Cao XJ;Jakus Z;Zheng H;Yang J;Arthur JS;Whitehead KJ;Li D;Zhou B;Garcia BA;Zheng X;Kahn ML
• 通讯作者: Kahn ML

Role of Rho-Associated Kinase in the Pathophysiology of Cerebral Cavernous Malformations.

• DOI: 10.1212/nxg.0000000000200121
• 发表时间: 2024-02
• 期刊: Neurology. Genetics

Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells.

• DOI: 10.1161/circresaha.118.313970
• 发表时间: 2018-10-26
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Detter MR;Snellings DA;Marchuk DA
• 通讯作者: Marchuk DA