Neurorestorative therapy of stroke with agents that increase HDL

使用增加 HDL 的药物进行中风的神经恢复治疗

• 批准号: 8435403
• 负责人: JIELI CHEN
• 金额: $ 27.01万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435403
• 关键词: Adult; Agonist; Angiogenic Factor; Angiopoietin-1; Angiostatins; Antibodies; Attenuated; Blood Vessels; Brain; Cerebrovascular Circulation; Cerebrum; Clinical; Data; Drug Formulations; Fostering; Health; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hour; Ischemic Stroke; Knockout Mice; Liver; Mediating; Middle Cerebral Artery Occlusion; Molecular; Morbidity - disease rate; Mus; Nervous System Physiology; Neurologic; Neurological outcome; Nicotinic Acids; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Recovery; Recovery of Function; Regulation; Rodent Model; Role; Safety; Serum; Signal Pathway; Signal Transduction; Stroke; TIE-2 Receptor; Testing; Therapeutic; Tissues; Toxic effect; Translations; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular remodeling; angiogenesis; base; design; disability; functional outcomes; human NOS3 protein; improved; neurorestoration; novel; pre-clinical; receptor; stroke therapy

DESCRIPTION (provided by applicant): High-density lipoprotein cholesterol (HDL-C) has a positive effect on endothelial cell and vascular wall function. To our knowledge, there are no studies investigating the use of increasing HDL-C as a neurorestorative therapy to promote brain plasticity and recovery of neurological function after stroke. Based on robust preliminary data that agents which increase HDL-C when administered starting one day after stroke, promote vascular remodeling and significantly reduce functional deficits after ischemic stroke, we seek to develop a novel neurorestorative treatment of ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate their molecular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo). Aim 1 will investigate safety, toxicity and neurorestorative effects of select agents which increase HDL-C after stroke in adult mice. We hypothesize that treatment of stroke in mice with agents that increase HDL-C {Niaspan (N) and TO901317 (T)} initiated at one day after stroke onset improves neurological functional recovery, and is safe and well tolerated. The minimally toxic and more effective agent (Niaspan or TO901317, N-or-T) that promotes functional outcome after stroke will be identified and will be employed in the following Aims 2 & 3. Aim 2 will elucidate the effect of N-or-T treatment of stroke on the regulation of angiogenic factors and vascular remodeling, i.e. cerebral blood flow (CBF), angiogenesis, and arteriogenesis. The contribution of vascular remodeling induced by N-or-T in functional outcome after stroke will be tested. We hypothesize that N-or-T treatment of stroke induces endothelial nitric oxide synthase (eNOS) and Angiopoietin-1(Ang1)/Tie2 signaling activity, which increase CBF, angiogenesis and arteriogenesis after stroke in mice. Inhibition of vascular remodeling by an anti-angiogenic factor, Angiostatin (K1-5), impairs functional outcome after stroke and attenuates the N-or-T induced restorative effect after stroke in mice. Aim 3 will identify the molecular signaling pathways by which N- or-T induces vascular remodeling and functional recovery after stroke. The contribution of eNOS and Ang1/Tie2 to N-or-T induced restorative effect and vascular remodeling will be examined by using eNOS knockout mice and a specific antibody to Tie2 in mice subjected to stroke and treated with N-or- T, respectively. The underlying hypotheses are that: Increasing HDL-C agent (N-or-T) fosters functional recovery after stroke by increasing the expression and activation of eNOS and Ang1/Tie2 signaling in cerebral tissue; these factors promote vascular remodeling via the induction of angiogenesis and arteriogenesis, which augment functional recovery. This study provides a new and highly effective way to treat stroke and may permit translation of our findings of the restorative therapeutic benefit of agents which increase HDL-C in experimental stroke to the patient.

DESCRIPTION (provided by applicant): High-density lipoprotein cholesterol (HDL-C) has a positive effect on endothelial cell and vascular wall function. To our knowledge, there are no studies investigating the use of increasing HDL-C as a neurorestorative therapy to promote brain plasticity and recovery of neurological function after stroke. Based on robust preliminary data that agents which increase HDL-C when administered starting one day after stroke, promote vascular remodeling and significantly reduce functional deficits after ischemic stroke, we seek to develop a novel neurorestorative treatment of ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate their molecular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo). Aim 1 will investigate safety, toxicity and neurorestorative effects of select agents which increase HDL-C after stroke in adult mice. We hypothesize that treatment of stroke in mice with agents that increase HDL-C {Niaspan (N) and TO901317 (T)} initiated at one day after stroke onset improves neurological functional recovery, and is safe and well tolerated. The minimally toxic and more effective agent (Niaspan or TO901317, N-or-T) that promotes functional outcome after stroke will be identified and will be employed in the following Aims 2 & 3. Aim 2 will elucidate the effect of N-or-T treatment of stroke on the regulation of angiogenic factors and vascular remodeling, i.e. cerebral blood flow (CBF), angiogenesis, and arteriogenesis. The contribution of vascular remodeling induced by N-or-T in functional outcome after stroke will be tested. We hypothesize that N-or-T treatment of stroke induces endothelial nitric oxide synthase (eNOS) and Angiopoietin-1(Ang1)/Tie2 signaling activity, which increase CBF, angiogenesis and arteriogenesis after stroke in mice. Inhibition of vascular remodeling by an anti-angiogenic factor, Angiostatin (K1-5), impairs functional outcome after stroke and attenuates the N-or-T induced restorative effect after stroke in mice. Aim 3 will identify the molecular signaling pathways by which N- or-T induces vascular remodeling and functional recovery after stroke. The contribution of eNOS and Ang1/Tie2 to N-or-T induced restorative effect and vascular remodeling will be examined by using eNOS knockout mice and a specific antibody to Tie2 in mice subjected to stroke and treated with N-or- T, respectively. The underlying hypotheses are that: Increasing HDL-C agent (N-or-T) fosters functional recovery after stroke by increasing the expression and activation of eNOS and Ang1/Tie2 signaling in cerebral tissue; these factors promote vascular remodeling via the induction of angiogenesis and arteriogenesis, which augment functional recovery. This study provides a new and highly effective way to treat stroke and may permit translation of our findings of the restorative therapeutic benefit of agents which increase HDL-C in experimental stroke to the patient.

项目成果

Models and mechanisms of vascular dementia.

• DOI: 10.1016/j.expneurol.2015.05.006
• 发表时间: 2015-10
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Venkat P;Chopp M;Chen J
• 通讯作者: Chen J

Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin.

• DOI: 10.1177/1535370213520109
• 发表时间: 2014-05
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Mali VR;Ning R;Chen J;Yang XP;Xu J;Palaniyandi SS
• 通讯作者: Palaniyandi SS

Deficiency of brain ATP-binding cassette transporter A-1 exacerbates blood-brain barrier and white matter damage after stroke.

• DOI: 10.1161/strokeaha.114.007145
• 发表时间: 2015-03
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Cui X;Chopp M;Zacharek A;Karasinska JM;Cui Y;Ning R;Zhang Y;Wang Y;Chen J
• 通讯作者: Chen J

Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats.

糖尿病大鼠中风的骨髓基质细胞治疗的不良影响。

• DOI: 10.1161/strokeaha.111.627174
• 发表时间: 2011-12
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Chen J;Ye X;Yan T;Zhang C;Yang XP;Cui X;Cui Y;Zacharek A;Roberts C;Liu X;Dai X;Lu M;Chopp M
• 通讯作者: Chopp M

Neamine induces neuroprotection after acute ischemic stroke in type one diabetic rats.

• DOI: 10.1016/j.neuroscience.2013.10.071
• 发表时间: 2014-01-17
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Ning R;Chopp M;Zacharek A;Yan T;Zhang C;Roberts C;Lu M;Chen J
• 通讯作者: Chen J