中國醫藥大學競爭性團隊研究中心計畫

中文計畫名稱 : L5 醫學研究中心

英文計畫名稱 : L5 Medical Research Center

主持人 單位 職稱總計畫 李源德 醫學系 講座教授

子計畫 1 馬明琪 分統所 教授子計畫 2 汪貴珍 國立中國醫藥研究所 教授子計畫 3 張坤正 醫學系 副教授

子計畫 4 施庭芳 台大附設醫院放射科

教授

子計畫 5 張永賢 針灸所 教授

整合型總計畫名稱： Identification of a Novel

Cardiovascular Risk Factor through a Translational

Approach

• Director: 李源德 講座教授• Co-Director: Chu-Huang Chen ( 陳珠璜 ), MD PhD,

Associate Professor, Baylor College of Medicine

The composition of a new cardiovascular research center at CMU-CMUH:

L5 Medical Research Center

What is L5?

LDL-C = 190 mg/dl LDL-C = 119 mg/dl

Electronegative LDL mildly oxidized in vivo.L5 is the most highly electronegative LDL.L5 can induce apoptosis of vascular endothelial cells.Endothelial apoptosis contributes to atherosclerosis and

thrombosis.

L5 composition and its distinction from HDL

Tang et al. ACC meeting in Chicago, April 1st 2008

Who has L5?

HypercholesterolemiaLDL-C >160 mg/dL

Metabolic SyndromeLDL-C all ranges

Type 2 DMLDL-C all ranges Chronic Smokers

LDL-C all ranges

L5

Interruption of the FGF2-PI3K-Akt Autoregulatory Loop by L5

Lu and Jiang et al. Diabetes 2008

Internalization of L5 and oxLDL by LOX-1 and endocytosis of L1 by LDLR

Role of LOX-1 in smoker L5 induced mitochondrial disruption

Chen’s labTang et al. ACC meeting in Chicago. April 1st 2008

Effect of Zetia on L5 reduction in hamster fed with high-fat diet

L5 UnoQ6 B 10ml HF001:10_UV L5 UnoQ6 B 10ml control001:10_UV L5 UnoQ6 B 10ml Zetia001:10_UV L5 UnoQ6 B 10ml HF001:10_Fractions

0

20

40

60

80

mAU

0 20 40 60 80 100 120 140 min

1 2 3 4 5 6 7 8 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75

HFHC diet + ezetimibe

Control (normal diet)

HFHC diet

L1 (%) L5 (%)Control (normal diet) 83.36 16.64

HFHC diet 57.74 42.26HFHC diet + ezetimibe 93.31 6.69

Morphological changes in EPC colonies with sustained exposure to L5 vs. L1

Goal and significanceof the new cardiovascular research center

• Goal– to establish an in vivo relevance of L5 in

atherosclerosis.• Significance

– Impact on public health in Taiwan– Impact on medical research in Taiwan

Missions of the core laboratory and all divisions

• Core Laboratory: ( 陳珠璜 Assoc. Prof; 楊朝諭教授 ) 黃志揚教授 汪貴珍教授 張博淵助理教授 李安生助理教授– will be providing L5 for cell and animal studies and

performing all L5 analyses– fully characterize L5 and strengthen the theoretical

basis for all the studies

• Division I—Cell Study Division ( 馬明琪教授 ; 李啟明副教授 ) 黃志揚教授 , 李宗貴教授 , 陳珠璜 Assoc. Prof– to provide further evidence of L5’s capability of deranging

the molecular homeostasis.– strengthen the theoretical basis for the animal and human

studies– provide insights into new targets for treatment

• 子計畫 : – Effects of L5 on macrophage physiology– Effects of L5 on endothelium-dependent vascular functions– Effects of L5 on the expression of adhesion molecules in

endothelial cells– Effects of L5 on hypertrophy and apoptosis in

cardiomyocytes

• Division II—Animal Study Division: ( 汪貴珍教授 , 郭薇雯副教授 ), 李安生助理教授 , 陳珠璜 Assoc. Prof– will be performing animal studies to establish the in vivo

relevance of L5 in atherosclerosis.– to provide sufficient evidence to establish such a cause-

effect relation.• 子計畫 :

– Induction of L5 synthesis in hamsters and investigation of the mechanism

– Effects of L5 on EDR in aortic ring preparations– Role of L5 in diabetic cardiomyopathy in rat models

• Division III—Clinical Study Division: ( 張坤正副教授 , 張博淵助理教授 ), 白培英醫師 , 張詩聖醫師 , 李源德講座教授 , 陳珠璜 Assoc. Prof– To establish clinical correlation between L5 and

atherosclerosis– To provide human plasma samples for L5 isolation and

purification at the core laboratory.• 子計畫 :

– L5 as a possible risk factor in CAD events • To test relationship of L5 with progress of atherosclerosis• To identify the specific modified lipids and/or proteins

/peptides in L5• To link to Pilot Clinical Trials with statin and Red rice

• Division IV—Imaging Study Division: ( 施庭芳教授 , 何永仁主任 ), 沈戊忠教授 , 李源德講座教授 , 張坤正副教授 , 陳珠璜 Assoc. Prof– to provide direct visual evidence of vascular disease in

humans – to establish a close correlation between L5 concentration

and tissue perfusion in humans by using DCE-MRI technology

• 子計畫 : – Correlation between plasma L5 levels and pancreatic

perfusion in humans

• Division V—Pilot Trial Study Division: ( 張永賢副校長 , 陳清助主任 ), 汪貴珍教授 , 郭薇雯副教授 , 王宇澄醫師 , 陳珠璜 Assoc. Prof– to identify natural products as alternative regiments for L5

reduction in high risk patients, and – to examine whether L5 reduction is accompanied by

clinical improvement of endothelial function. The two products to be tested are Monascus purpureus ( 紅麴 ) and garlic extract ( 大蒜 ).

• 子計畫 : – Effect of Monascus purpureus on L5 reduction in patients

with T2DM– Effect of garlic on L5 reduction in patients with T2DM

THANK YOU FOR YOUR ATTENTION!