Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease

项目概要/摘要 外周动脉疾病（PAD）是由下肢动脉粥样硬化引起的， 一系列改变生命的疾病，包括跛行、缺血性静息痛和坏疽， 截肢PAD的病因复杂化，患者通常存在合并症或风险 加速疾病演变和显著恶化病理导致死亡率增加的因素 风险其中，慢性肾脏病（CKD）加速动脉粥样硬化的发展，降低 功能能力，并增加截肢或死亡的风险，但潜在的生物学机制 与其他合并症（即吸烟和糖尿病）相比，对糖尿病的了解很少，研究也非常不足。 我们已经发现了一种新的分子途径，可能连接CKD和PAD的病理生物学。我们发现很多 尿毒症代谢物在CKD中蓄积，导致芳烃受体（AHR）的慢性激活 这导致线粒体电子传递系统的破坏， 损伤并损害血管生成。初步实验表明，AHR的基因敲除是 对尿毒症毒性的保护，而组成型活性AHR的表达导致线粒体 功能障碍因此，我们建议测试新的假设，慢性激活的AHR途径， 导致缺血性肌肉损伤和血管生成受损，从而将CKD和PAD病理学联系起来。这 将使用肌肉和血管特异性诱导敲除AHR以及腺病毒基因来检验这一假设。 在CKD/PAD的临床前模型中相关病毒介导的组成型活性AHR的表达。 最后，我们最近的人类数据表明，在PAD患者CKD升高AHR信号。我们建议 扩展这些发现，以建立肌肉健康/功能，线粒体能量学和 人类PAD患者中的AHR信号传导。这些研究的成功将为我们提供关于 CKD对PAD病理学的影响，并将为旨在 治疗目前几乎没有可用选择的患者群体。

PROJECT SUMMARY/ABSTRACT Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Complicating the etiology of PAD, patients typically present with comorbid conditions or risk factors that accelerate disease evolution and substantially worsen pathology contributing to increased mortality risk. Among these, chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases functional capacity, and increases risk of amputation or death, however the underlying biologic mechanism(s) are poorly understood and vastly understudied compared with other comorbidities (i.e. smoking and diabetes). We have uncovered a novel molecular pathway that may link CKD and PAD pathobiology. We find that many uremic metabolites, which accumulate in CKD, cause chronic activation of the aryl hydrocarbon receptor (AHR) which leads to disruption of the mitochondrial electron transport system that exacerbates ischemic muscle injury and impairs angiogenesis. Preliminary experiments demonstrate that genetic knockdown of the AHR is protective against uremic toxicity, whereas expression of a constitutively active AHR causes mitochondrial dysfunction. Thus, we propose to test the novel hypothesis that the chronic activation of the AHR pathway results in ischemic muscle injury and impaired angiogenesis, thereby linking CKD and PAD pathobiology. This hypothesis will be tested using muscle- and vascular-specific inducible knockout of the AHR as well as adeno- associated virus-mediated expression of the a constitutively active AHR in pre-clinical models of CKD/PAD. Finally, our recent human data indicate elevated AHR signaling in PAD patients with CKD. We propose to extend these findings to establish a clinical link between muscle health/function, mitochondrial energetics, and AHR signaling in human PAD patients. Success in these studies will provide mechanistic insight into the impact of CKD on PAD pathobiology, and would provide a novel target for therapeutic development aimed to treat a patient population that currently has few available options.