Unraveling the Pathogenic Mechanism of Blood Reflux in Varicose Vein

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簡歷

基本資料

Project title

Code/計畫編號

MOST107-2320-B157-001

Translated Name/計畫中文名

闡明血液逆流對靜脈曲張的致病機制

Project Coordinator/計畫主持人

Ding-Yu Lee

Funding Organization/主管機關

National Science and Technology Council

Department/Unit

The Department of Biological Science and Technology,CUST

Website

https://www.grb.gov.tw/search/planDetail?id=12423767

Year

2018

Start date/計畫起

01-05-2018

Expected Completion/計畫迄

01-04-2019

Bugetid/研究經費

1200千元

ResearchField/研究領域

其他（醫）

靜脈曲張具有高發生率且會產生更嚴重的靜脈疾病，為重要臨床問題。血液逆流產生的擾流被認為會導致靜脈曲張。在動脈中，擾流被認為是”壞流體”造成動脈血管內皮病變，Smad-1/5/8為此過程中重要致病因子。然而，Smad-1/5/8在靜脈病變的角色仍屬未知。本計畫將使用體外流體實驗及病人檢體全面性研究Smad-1/5/8及其相關訊息分子在擾流誘導靜脈曲張血管內皮病變過程中的角色，進而發展診斷及治療方式。我們初步結果顯示p-Smad-1/5/8及VCAM-1會大量表現於有血液逆流的靜脈曲張血管，而非正常靜脈血管。我們接著將從不同期別靜脈病變病人身上取得逆流血管及血清，研究Smad-1/5/8及VCAM-1在靜脈內皮病變過程的表現情形及血液中Smad作為檢測分子的可能性。建立體外流體系統產生擾流 vs. 平順流研究擾流對Smad-1/5/8及靜脈內皮病變 (增生、氧化、發炎)的影響及致病機制。人類病變血管亦將證實Smad-1/5/8相關訊息分子在靜脈曲張病變過程所扮演的功能及角色。最後，Smad-1/5/8及相關訊息分子的抑制劑將被發展為以血液動力學為基礎的靜脈曲張治療藥物。抑制劑安全性亦將被MTT assay所證實。本計畫不但將幫助我們了解Smad-1/5/8在人類靜脈曲張病變過程所扮演的角色，也將提供Smad-1/5/8調節擾流誘導靜脈血管內皮病變的詳細機制，進而發展以血液動力學為基礎的”嶄新”抗靜脈曲張藥物及診斷方式。Varicose vein is the common venous disease, which has high prevalence and recurrence rate. More than 20% of varicose patient develop advanced chronic venous disease (CVD). Thus, varicose vein has severe clinical and social problems in the worldwide. Understanding the detailed mechanism of varicose vein progression to develop clinical applications is urgent to solve these problems. Blood reflux with disturbed flow is well recognized to be the predominant determinant to induce CVD or varicose vein. In arotic system, Smad-1/5/8 have been identitified as the vital hemodynamics-spcific pathogenic factors for modulating aortic EC dysfunction. However, the roles of Smads in venous EC disorders, i.e. CVD or varicose vein, remain unclear. In addition, the clinically diagnostic and therapeutic applications of Smad for venous disorders still need to be defined. In present study, we will use the comprehensive approaches from in vitro flow experiments to human clinical specimens from CVD patients to elucidate the in vivo functional roles of Smad-1/5/8 and their related signaling molecules in disturbed flow-induced EC dysfunction in the pathogenesis of human CVD or varicose vein and develop clinical applications for human CVD. Our preliminary results showed that the expressions of p-Smad 1/5/8 and inflammatory VCAM-1 are up-regulated in venous EC of human varicose vein with blood reflux compared to varicose vein without blood reflux and normal vein. These results suggest that Smad-1/5/8 and VCAM-1 may also be the hemodynamics-regulated pathogenic factors for CVD or varicose vein. We further will collect the human specimens and fresh blood from different stages of CVD patients with blood reflux or without reflux and healthy subjects to identify the in vivo functional roles of Smad 1/5/8 and VCAM-1 in blood reflux-induced venous disorders in the progression of CVD and develop serum Smads as diagnostic components for CVD. In vitro flow system will be developed to generate the different flow patterns, i.e. laminar flow vs. disturbed flow, to mimic those existed in healthy subjects vs. CVD patients and identify the effects of different flow patterns on modulating Smad-related signaling and venous EC dysfunction, including proliferation, oxidation, and inflammation. The detailed mechanism involved in shear-modulated Smad signaling and venous EC dysfunction will also be defined. Moreover, the diseased veins from human patients in the different stage of CVD with blood refux or without reflux and normal veins will be collected to confirm the in vivo functionl roles of identified Smad signaling molecules in disturbed flow-induced venous disorder. Finally, the inhibitors of Smad-1/5/8 or Smad-related signaling molecules will be developed as hemodynamics-based therapeutic components for human CVD treatment. The safety of these therapeutic components will be confirmed by MTT assay. The information provided in this proposed research will help us to identify not only the in vivo functional role of Smad-1/5/8 in the progression of human CAD and varicose vein, but also its underlying mechanism in modulating disturbed flow-induced EC dysfunction. Furthermore, we will develop the inhibitors of Smad signaling as “Novel” therapeutic components and serum Smad as “New” diagnostic components for human CVD or varicose vein.

Keyword(s)

靜脈曲張
慢性靜脈疾病
血液逆流
擾流
靜脈內皮細胞病變
aricose vein
chronic venous disease
blood reflux
disturbed flow
venous endothelial cell dysfunction.

DSpace CRIS

Unraveling the Pathogenic Mechanism of Blood Reflux in Varicose Vein

基本資料

Description