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Protein homeostasis dysfunction in LM and VM pathobiology and therapeutic responses

LM 和 VM 病理学和治疗反应中的蛋白质稳态功能障碍

基本信息

批准号：
10567637
负责人：
CARRIE J. SHAWBER
金额：
$ 62.34万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567637
关键词：
Affect Animal Model Blood Blood Coagulation Disorders Blood Vessels Bortezomib Cell Death Cell Separation Cell physiology Cell surface Cells Classification Clinical Collaborations Congenital Abnormality Cytoplasm Dangerousness Data Deep Vein Thrombosis Defect Degradation Pathway Development Dose Drug Screening Endosomes Endothelial Cells Equilibrium FDA approved FRAP1 gene Functional disorder Genes Genetic Goals Grant Growth Heart Diseases Hemorrhage Human In Vitro Infection KRAS2 gene KRASG12D Label Lesion Life Link Lymphatic Lymphatic Endothelial Cells Lysosomes MAPK Signaling Pathway Pathway Malignant Neoplasms Medical Morbidity - disease rate PECAM1 gene PI3K/AKT PIK3CA gene PIK3CG gene Pain Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phenocopy Principal Investigator Production Proteasome Inhibition Proteasome Inhibitor Protein Biosynthesis Proteins Pulmonary Fibrosis Ras/Raf Reporting Research Risk Role Sepsis Signal Transduction Sirolimus Somatic Mutation Therapeutic Intervention Transgenic Mice Transgenic Organisms Variant Vascular System Venous Venous Malformation Xenograft Model alpelisib cellular engineering clinically relevant efficacy evaluation functional improvement genetic variant improved lymphatic malformations lymphatic vasculature malformation mortality mosaic mouse model multicatalytic endopeptidase complex novel drug class novel therapeutics overexpression partial response programs protein degradation proteostasis response success targeted treatment therapeutic target treatment response

项目摘要

SUMMARY Slow flow vascular malformations, including lymphatic malformations (LMs) and venous malformations (VMs), have been shown to be caused by somatic mutations in genes that hyperactivate the PI3K/mTOR or RAS signaling. LM/VM patients have severe morbidities and even mortality, and there are no FDA-approved treatments. Current therapies provide partial response and are non-curative. There is an urgent need to identify effective, biologically targeted therapeutics. We have discovered protein homeostasis dysfunction in pathogenic endothelial cells (ECs) isolated from LMs (LMECs) and VMs (VMECs). We demonstrate that this dysfunction is downstream of PI3K/mTOR hyperactivation, which results in increased VECADHERIN and CD31 synthesis, cytoplasmic accumulation, and decreased expression at the cell surface. We proposed that the excess of VECADHERIN/CD31 in the cytoplasm overwhelms the proteasome and lysosomal degradation pathways, which in turn perturbs VECADHERIN/CD31 functions essential to the quiescent blood and lymphatic vasculature. Supporting this hypothesis, we identified a novel class of drugs, proteasome inhibitors (PIs) that inhibit proteasome degradation and preferentially target cells with protein homeostasis defects as more efficacious at suppressing LMEC/VMECs growth when compared to currently used therapies. We hypothesize that PI3K hyperactivation induces protein homeostasis defects that contribute to LM/VM pathology and that targeting this dysfunction serves as a new avenue of therapeutic intervention. In Aim 1, we will determine the mechanism by which PIs suppress abnormal LM and VM growth using patient derived LMEC/VMECs with PI3K and/or RAS pathway hyperactivation. Transgenic mouse models that express either PIK3CAH1047 or KRASG12D using EC and LEC specific drivers will be used to assess the efficacy of 2 PIs, oprozomib and bortezomib, with a goal of prioritizing which PI can be repurposed for the treatment of LMs and VMs. In Aim 2, we will determine the role of protein homeostasis dysfunction in VM/LM pathobiology. Primary human ECs that overexpress pathogenic PIK3CA or KRAS variants and patient ECs will be used to understand the consequences and mechanisms by which increased VECADHERIN and CD31 expression and cytoplasmic accumulation overwhelms proteasome and lysosomal degradation pathways. We will also determine if drugs that improve protein degradation can normalize LMEC/VMEC pathology. The goal is to better understand how common pathogenic variants in LM/VMs contribute to their pathogenesis and determine if therapeutics that target protein degradation defects can be repurposed for LM/VM patients.

总结