Regulation of angiogenesis by nuclear receptors and cofactors

核受体和辅助因子对血管生成的调节

• 批准号: 9478309
• 负责人: VIHANG A NARKAR
• 金额: $ 41.14万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-02 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478309
• 关键词: Affect; American; Angiogenic Factor; Area; Binding; Biological Assay; Blood Vessels; Cardiovascular Diseases; Chronic; Complication; Conditioned Culture Media; Data; Development; Diabetes Mellitus; Disease; Double Effect; Endothelial Cells; Fibrinogen; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Impaired wound healing; Impairment; In Vitro; Individual; Ischemia; Knock-out; Knockout Mice; Lead; Limb structure; Measures; Mediating; Metabolic Diseases; Molecular; Mus; Muscle; Muscle Cells; Muscular Atrophy; Myocardial Infarction; Myopathy; Names; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Nuclear Receptors; Operative Surgical Procedures; PPAR gamma; Paracrine Communication; Pathologic; Pathology; Patients; Peripheral arterial disease; Pharmacologic Substance; Prevalence; Regulation; Regulator Genes; Repression; Research; Research Proposals; Role; Severities; Site; Skeletal Muscle; Stroke; Symptoms; Testing; Transgenic Mice; Tumor Angiogenesis; Ulcer; Vascular Endothelial Growth Factors; Vascular blood supply; Vascularization; Work; angiogenesis; chicken ovalbumin upstream promoter-transcription factor; cofactor; cost; db/db mouse; diabetic; disabling symptom; experimental study; hypoxia inducible factor 1; improved; in vivo; innovation; knock-down; limb amputation; new therapeutic target; overexpression; paracrine; prevent; programs; public health relevance; receptor; reconstruction; skeletal muscle wasting; therapeutic angiogenesis; treatment strategy; vessel regression

 DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) and its severe form critical limb ischemia (CLI) affect nearly 8 million Americans. Most patients with chronic metabolic and cardiovascular diseases such as diabetes also suffer from PAD/CLI. Patients with PAD/CLI suffer from debilitating symptoms such as immobility, ulceration, impaired wound healing, and intractable ischemia. The pathology of PAD/CLI involves vascular regression in the skeletal muscle, which leads to significant myopathy. Treatment is limited to surgical reconstruction, which is often costly and ineffective leading to limb amputations. 'Therapeutic angiogenesis' to improve muscle vascular supply is an urgent area of research in PAD/CLI. Within this field, focus has been on pro-angiogenic regulators such as vascular endothelial growth factor-alpha (Vegfa) and hypoxia inducible factor 1 (HIF1), and how they can improve muscle vasculature. Unfortunately, individual angiogenic factors and even HIF1 have so far been ineffective targets in PAD/CLI. Notably, skeletal muscle vascular supply and neo angiogenesis is controlled in a paracrine fashion by both pro-angiogenic and anti-angiogenic factors secreted by the muscle. While molecular regulation of pro-angiogenic factors such as Vegfa in the muscle is defined, surprisingly, the molecular regulation of anti-angiogenic factors is poorly defined. We have preliminarily found that a transcriptional cofactor peroxisome proliferator-activated receptor gamma co-activator 1 beta (PGC1β), which typically functions by activating nuclear hormone receptors, encodes an inhibitory angiogenesis gene program in the skeletal muscles. This program constitutes induction of anti-angiogenic factors and repression of proangiogenic factors, resulting in a net inhibition of skeletal muscle revascularization in ischemia. Interestingly, we found that PGC1β expression is induced along with the anti-angiogenic factors in diabetic muscles, which are characterized by the pathological symptoms of PAD/CLI such as vascular regression, ischemia and impaired neo-angiogenesis. Therefore, the first objective of this research proposal is to decipher the role of endogenous muscle PGC1β in regulating inhibitory angiogenic program and its effect on ischemic muscle revascularization and diabetic muscle angiopathy. The second objective is to establish COUP-TFI (chicken ovalbumin upstream promoter transcription factor I) as the nuclear receptor involved in PGC1β-driven inhibitory angiogenesis. Our preliminary data indicates that the anti-angiogenic effects of PGC1β may be mediated by activating nuclear receptor COUP-TFI. Our central hypothesis is that PGC1β in the skeletal muscle instigates a paracrine anti-angiogenic gene program by activating COUP-TFI, blocks ischemic neo angiogenesis, and contributes to diabetic muscle angiopathy. The specific aims to test this hypothesis are to: (Aim 1) Investigate the role of endogenous PGC1β in muscle angiogenesis and (Aim 2) Investigate whether PGC1β and COUPTFI interact to regulate muscle angiogenesis. In Aim 1, we will use muscle-specific deletion of PGC1β in mice to investigate how the loss of muscle PGC1β affects muscle vasculature, ischemic revascularization and the expression of angiogenic factors. In Aim 2, we will first perform in vitro experiments to study the interaction between PGC1β and COUP-TFI, and how they regulate muscle angiogenic genes. Second, we will use muscle-specific compound transgenic mice to investigate whether the anti-angiogenic effects of musclespecific PGC1β over-expression is lost on muscle-specific COUP-TFI deletion. We will also investigate the impact of double muscle-specific PGC1β and COUP-TFI knockout on muscle neo-angiogenesis and revascularization. The significance of our work is that it aims to discover how anti-angiogenic gene program is regulated in the skeletal muscle, and how it affects revascularization in muscle ischemia and diabetic muscle angiopathy. Our research is innovative as we will study the unexplored area of anti-angiogenic gene programming in the treatment of PAD/CLI. The findings will have implications for devising new treatment for muscle ischemia in PAD/CLI, and broadly in other diseases such as cardiac infarction, stroke and tumor angiogenesis.



项目成果

PGC1α Promoter Methylation and Nucleosome Repositioning: Insights Into Exercise and Metabolic Regulation in Skeletal Muscle.

PGC1α 启动子甲基化和核小体重新定位：深入了解骨骼肌的运动和代谢调节。

• DOI: 10.1210/en.2017-00439
• 发表时间: 2017
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Narkar,VihangA

Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting.

• DOI: 10.1038/s41598-017-10238-9
• 发表时间: 2017-08-31
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Sopariwala DH;Yadav V;Badin PM;Likhite N;Sheth M;Lorca S;Vila IK;Kim ER;Tong Q;Song MS;Rodney GG;Narkar VA
• 通讯作者: Narkar VA

Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice.

• DOI: 10.1038/srep26442
• 发表时间: 2016-05-25
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Badin PM;Vila IK;Sopariwala DH;Yadav V;Lorca S;Louche K;Kim ER;Tong Q;Song MS;Moro C;Narkar VA
• 通讯作者: Narkar VA