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Decoding the Molecular and Cellular Mechanisms of Mutant KRAS-driven Brain Arteriovenous Malformations

解读突变 KRAS 驱动的脑动静脉畸形的分子和细胞机制

基本信息

批准号：
10446836
负责人：
Jason Fish
金额：
$ 67.2万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446836
关键词：
Adult Affect Anatomy Angiogenic Factor Animal Disease Models Animal Model Arteries Behavioral Assay Biology Blood Vessels Blood capillaries Blood flow Brain Neoplasms Brain hemorrhage Caliber Cell Culture Techniques Cell Shape Cells Cellular Morphology Cellular biology Cerebral cortex Cessation of life Child Clinical Cognition Cognitive Cues Cultured Cells Cytoskeleton Data Development Diagnosis Disease Down-Regulation Endothelial Cells Endothelium Etiology Event Extracellular Matrix FDA approved Family history of Frequencies GTP Binding Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Hemorrhage Histologic Histology Homeostasis Human Hypertension Hypoxia Image Immunohistochemistry In Vitro Intervention KRAS2 gene Knowledge Label Lesion MEK inhibition MEKs Maintenance Medical Minority Mitogen-Activated Protein Kinases Modality Modeling Molecular Molecular Target Monomeric GTP-Binding Proteins Morbidity - disease rate Mosaicism Movement Mus Mutation Neuraxis Neurofibrillary Tangles Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Patient-Focused Outcomes Patients Pericytes Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Process Publishing Radiation Resistance Risk Rupture Sampling Severity of illness Shunt Device Signal Transduction Smooth Muscle Myocytes Stress Stroke Testing Therapeutic Embolization Time Vascular Smooth Muscle Vascular remodeling Veins Zebrafish brain arteriovenous malformations cadherin 5 cell behavior design disability risk exome sequencing feeding functional disability hemodynamics high risk improved in vivo inhibitor insight malformation mutant neuron loss novel novel therapeutics optogenetics prevent recruit response sensor shear stress single-cell RNA sequencing surgical risk therapeutic target transcriptomics vascular bed young adult

项目摘要

SUMMARY Brain arteriovenous malformations (bAVMs) are composed of abnormal connections between arteries and veins that lack an intervening capillary network. As a result, high-pressure blood from feeding arteries shunts directly into veins. These vascular lesions become distended and highly remodeled, resulting in a tangle of enlarged blood vessels that are prone to rupture. Indeed, bAVMs are a leading cause of hemorrhagic stroke in children and young adults. All current treatment modalities for bAVMs, including surgery, embolization or radiation carry a significant risk of disability or death, and these options are not available for ~20% of bAVM patients due to excessive risk. Because of these complications, alternative medical strategies with lower morbidities such as targeted pharmacological therapies are desperately needed. However, we first need a clear understanding of the biology underlying bAVM development and maintenance. The majority of bAVMs occur sporadically without a family history of the disease. Using whole exome sequencing, we recently identified somatic, activating mutations in the KRAS gene, which encodes a GTPase that is involved in signal transduction. The identified mutations were confined to the endothelium and result in KRAS being locked in a GTP-bound ‘ON’ state. Notably, we have established mouse and zebrafish models of endothelial-specific expression of mutant KRAS, which have revealed the sufficiency for these genetic lesions to drive disease. We have gone on to demonstrate, through transcriptional profiling of cultured cells and in vivo studies in zebrafish expressing mutant KRAS, that many KRAS-induced molecular and cellular changes require MEK/ERK activity. Much remains to be learned regarding the etiology of sporadic bAVMs and our cell culture, mouse and zebrafish models will enable us to define the molecular, cellular and morphological changes that are involved in the initiation and maintenance of bAVMs. We will utilize our expertise in animal models of bAVMs, imaging, cell biology, signaling and single-cell RNA sequencing, to gain unprecedented insight into the bAVM disease process. This information will be leveraged for the design of pharmacological interventions to improve patient outcomes. Our proposal will: 1) define the threshold of KRAS mutant endothelial cells that can remodel vessels, 2) identify the vascular bed(s) that are susceptible to active KRAS expression, 3) determine how KRAS mutations impact hemodynamic signaling and bAVM progression, 4) uncover the cell-autonomous and non-cell autonomous mechanisms of mutant KRAS, and 4) determine the requirement for KRAS and MEK activation for bAVM maintenance in our pre-clinical models. Together, these studies will expand our understanding of bAVM pathogenesis and will assess whether inhibition of the KRAS/MEK pathway may be a viable therapeutic target to pursue in human patients with bAVM.

总结