哈佛大学科学家Huang受聘清华附属医院

生物谷

        清华大学第一附属医院于3月2日正式聘请在美国医学界享有盛誉的Paul L.Huang医生为生物科技和新药开发的首席科学家。

　　这是清华大学第一附属医院在建立了高水平的心脏中心、泌尿医学中心、消化医学中心基础上，围绕发展生命科学的战略，发挥多学科综合优势，整合国内外优质资源，高起点打造中国生物科技国际合作平台的一个重要举措。

　　Paul L.Huang医生毕业于哈佛大学医学院，在哈佛大学麻省总院学习和工作20余年，在新药开发、医学研究及各种临床心血管病的治疗上具有丰富经验，在美国医学界享有盛誉。一些美国专注于生物科技和新药开发的风险基金和财团此次也随Paul L.huang医生一起访问清华大学和第一附属医院。

　　Paul L.Huang医生的受聘标志着清华大学第一附属医院与哈佛大学医学院麻省总院里程碑式的合作，将推动两院医学合作，提高生物科技研究水平。

实验室网址: http://www.massgeneral.org/cvrc/crvc/huang.html

Dr. Huang's laboratory uses molecular, genetic, and genomic approaches to address important questions in cardiovascular medicine. We study the biological roles of nitric oxide (NO) in the control of cerebrovascular blood flow, cardiovascular hemodynamics, and the development of atherosclerosis.

We are using knockout and transgenic mouse models for the various NOS isoforms to define their specific roles. Neuronal NOS mutant mice have grossly enlarged stomachs due to abnormal pyloric sphincter relaxation, and serve as an animal model for the human disorder infantile pyloric stenosis. They are resistant to focal and global cerebral ischemia, demonstrating that neuronal NOS is involved in tissue injury following stroke. Endothelial NOS mutant mice provide genetic evidence that eNOS is responsible for the generation of endothelium-derived relaxing factor (EDRF). The mice are hypertensive, indicating the importance of endothelial NOS to blood pressure regulation. Using left ventricular catheterization and physiologic monitoring, we found that eNOS mutant mice show enhanced cardiac contractility to beta adrenergic stimulation, confirming a role for the endothelial NOS isoform in the physiologic regulation of cardiac function.

We are currently further refining the genetic manipulation of the NOS system by making tissue-specific knockout mice using Cre recombinase and loxP approaches. We are also making knock-in and transgenic mice that carry specific mutations, such as the S1179A and S1179D mutations of eNOS that alter Akt kinase phosphorylation sites.

Examples of current projects include:

NOS isoforms in atherosclerosis
eNOS deficiency worsens the atherosclerotic phenotype in apoE knockout mice fed a Western type diet. Moreover, apoE/eNOS double knockout mice develop aortic aneurysms, aortic dissection, distal coronary artery disease, and myocardial infarction, mimicking the human complications of atherosclerosis. We are combining in vivo models of vessel injury with diet-induced atherosclerosis to define the roles of various cell types and NOS isoforms in atherogenesis. apoE/eNOS double knockout mice (middle) develop more atherosclerotic lesions and abdominal aortic aneurysms compared with apoE knockout mice (left). Arrows show the location of the left renal artery. ApoE/eNOS double knockout mice also develop aortic dissection (right).

Cerebral ischemia
While nNOS is involved in tissue damage in ischemic and reperfusion injury, eNOS plays protective roles in maintaining cerebral blood flow in vulnerable areas. Both nNOS and eNOS isoforms are important to ischemic preconditioning, and activate the Ras/Raf/MEK/ERK pathways and the PI3 kinase/Akt pathways. We are studying the importance of these pathways to neuronal protection and ischemic preconditioning.

Figure 2 caption:
In collaboration with Dr. Dunn and Dr. Boas, we are examining dynamic blood flow in eNOS mutant mice using the laser speckle technique they developed. A. white light image. B. normal blood flow by laser speckle. C. blood flow under focal ischemic conditions by laser speckle.

For further information, contact:

Paul L. Huang, MD
Phone: (617) 724-9849
Fax: (617) 726-5806
E-mail: huangP@helix.mgh.harvard.edu

文章:

Huang PL. Unraveling the links between diabetes, obesity, and cardiovascular disease.
Circ Res. 2005 Jun 10;96(11):1129-31

Huang PL. Nitric oxide and cerebral ischemic preconditioning.
Cell Calcium. 2004 Sep-Oct;36(3-4):323-9.

Kuhlencordt PJ, Rosel E, Gerszten RE, Morales-Ruiz M, Dombkowski D, Atkinson WJ, Han F, Preffer F, Rosenzweig A, Sessa WC, Gimbrone MA Jr, Ertl G, Huang PL. Role of endothelial nitric oxide synthase in endothelial activation: insights from eNOS knockout endothelial cells.
Am J Physiol Cell Physiol. 2004 May;286(5):C1195-202.

Meck JV, Waters WW, Ziegler MG, deBlock HF, Mills PJ, Robertson D, Huang PL. Mechanisms of postspaceflight orthostatic hypotension: low alpha1-adrenergic receptor responses before flight and central autonomic dysregulation postflight.
Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1486-95

Huang PL. Endothelial nitric oxide synthase and endothelial dysfunction.
Curr Hypertens Rep. 2003 Dec;5(6):473-80.

Atochin DN, Clark J, Demchenko IT, Moskowitz MA, Huang PL. Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases.
Stroke. 2003 May;34(5):1299-303.

Gyurko R, Leupen S, Huang PL. Deletion of exon 6 of the neuronal nitric oxide synthase gene in mice results in hypogonadism and infertility.
Endocrinology. 2002 Jul;143(7):2767-74.

Chen J, Kuhlencordt PJ, Astern J, Gyurko R, Huang PL. Hypertension does not account for the accelerated atherosclerosis and development of aneurysms in male apolipoprotein e/endothelial nitric oxide synthase double knockout mice.
Circulation. 2001 Nov 13;104(20):2391-4.