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OPA1 an Estrogen-Mediated Modulator of Platelet Hyperactivation

OPA1 是雌激素介导的血小板过度活化调节剂

基本信息

批准号：
10614311
负责人：
E Dale Abel
金额：
$ 73.35万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2022-05-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10614311
关键词：
Address Animal Model Animals Bioenergetics Biological Models Blood Platelets Collaborations Complement Complex Contraceptive Usage Coronary Arteriosclerosis Coronary heart disease Data Diabetes Mellitus Epidemiology Estrogen Replacements Estrogens Exhibits Exposure to Female Follow-Up Studies Gene Expression Gonadal Steroid Hormones Hemostatic Agents Hormones Human Impairment In Vitro Inner mitochondrial membrane Iowa Knock-out Knockout Mice Knowledge Link Mediating Megakaryocytes Membrane Proteins Messenger RNA Metalloproteases Mitochondria Modeling Molecular Morphology Mus OPA1 gene Optic Atrophy Oral Contraceptives Ovariectomy Participant Patients Pattern Peptide Hydrolases Phase Phenotype Physiological Platelet Activation Platelet aggregation Postpartum Period Pregnancy Pregnant Women Premenopause Proteins Recording of previous events Risk Role Signal Pathway Signal Transduction System Testing Third Pregnancy Trimester Thrombosis Time Transcript Transgenic Mice Universities Utah Venous Thrombosis Woman Work Zinc base cohort genetic manipulation human model human pluripotent stem cell human subject in vivo in vivo Model indexing induced pluripotent stem cell innovation male metabolomics molecular phenotype mouse model next generation novel novel marker overexpression pill platelet function platelet phenotype pregnant programs recruit response sex thrombotic thrombotic complications transcriptome sequencing transcriptomics venous thromboembolism

项目摘要

Strong epidemiological evidence links pre-menopausal estrogen exposure to increased risk of venous thrombosis in women, particularly during pregnancy, in the immediate postpartum period, and in women taking estrogen-containing oral contraceptives (OCP). This proposal addresses a significant knowledge gap linking estrogens with platelet activation. Studies in the past have focused on how estrogens alter the hemostatic and fibrinolytic system. This proposal, which focuses on platelets, represents a productive collaboration between the Universities of Iowa and Utah. Our preliminary studies in the Framingham cohort and in pregnant humans, reveal increased platelet OPA1 levels in females, that predict risk of coronary artery disease, or correlate with increased platelet activation in the third trimester of pregnancy. In platelet-deficient OPA1 knockout (KO) mice we discovered that female OPA1KO mice were protected from thrombosis compared to males. The thrombosis phenotype was reversed after oophorectomy. Based on these preliminary findings, we hypothesize that OPA1 and regulators of OPA1 activity, OMA1 and YMEL1, modulate platelet activation in an estrogen-dependent manner and OPA1 levels in platelets predict estrogen modulated platelet activation. To address this hypothesis in the R61 phase, Aim 1 will determine the molecular mechanisms for estrogen-mediated and OPA-1-dependent modulation of platelet activation using mice with platelet specific OPA1 deletion and will generate OMA1 and YMEL1 platelet specific KO mice, with increased OPA1 activity. Aim 2 will determine platelet OPA1, OMA1, and YMEL1 expression and correlate expression levels to platelet activation in the setting of pregnancy and OCP use. We will also develop a human iPSC model system to generate MKs to determine if estrogen directly regulates the expression of these genes. The R33 phase will dissect the molecular mechanisms linking increased OPA1 with platelet activation in females. Aim 1 will perform detailed physiological and molecular phenotyping of murine platelets isolated from OMA1 and YMEL1 KO and OPA overexpressing transgenic mice. In addition, we will examine the mechanisms linking increased OPA1 activity, mitochondrial energetics and platelet activation. Aim 2 will complement animal studies by examining changes in mitochondrial function and signaling in platelets from pregnant women and women on OCPs. We will genetically ablate OMA1 and YMEL1 from iPSC-derived MKs to directly test if estrogen modulates MK and platelet function in an OPA1 dependent manner. By integrating in vivo and in vitro studies in humans and mouse models, our approach is translational, innovative and highly responsive to the RFA. These studies will determine for the first time whether increased estrogen exposure in pregnancy and OCP use reprogram MKs and developing platelets to increase thrombotic complications and identify novel mechanisms for this increased risk. The impact of these studies, is that they may identify novel biomarkers that may predict increased risk of thrombosis in susceptible females during pregnancy or prior to OCP use.

强有力的流行病学证据表明，绝经前雌激素暴露与静脉血栓形成风险增加有关