Negative Regulation of VEGF-Mediated Angiogenesis

描述（由申请人提供）：最近出现的一类抗癌疗法专注于阻断新血管的生长或血管生成，这是支持肿瘤生长所必需的。这一建议是基于一个独特的人群，唐氏综合征患者提供的临床线索，并试图确定在唐氏综合征人群中观察到的癌症保护的分子机制。流行病学资料表明，21号染色体上存在3个拷贝的一个基因通过控制肿瘤发生的某些共同方面发挥广泛的抗癌作用。本研究的重点是该活性的一个有希望的候选基因-唐氏综合症候选区域1 （Dscr1）基因。Dscr1基因编码一种蛋白，该蛋白通过负性调节vegf -钙调磷酸酶信号传导来阻断血管生成，特别是内皮细胞活化。我们假设唐氏综合征中Dscr1的三体表达通过减弱vegf -钙调磷酸酶- nfat信号和限制肿瘤血管生成来抑制肿瘤生长。在Specific Aim 1中，我们将使用我实验室最近生成的基因工程小鼠模型来确定DSCR1的过表达是否负责抑制唐氏综合征的肿瘤生长。在特异性目标2中，我们将研究血小板反应蛋白-1 （TSP-1）在调节肿瘤血管生成中的作用，TSP-1是我实验室最近发现的内皮细胞中vegf -钙调磷酸酶- nfat信号传导的靶标。我们将确认VEGF-钙调神经磷酸酶信号调控Tsp-1的机制，并确定其在调节VEGF促血管生成作用中的作用。我们还将确定内皮细胞中Tsp-1缺失对VEGF信号传导的影响。在Specific Aim 3中，我们将利用生化和突变相结合的方法和小鼠可移植肿瘤模型，确定DSCR1和药理学钙调神经磷酸酶抑制剂环孢素A阻断钙调神经磷酸酶功能的不同机制。提出的实验将利用这一临床见解来获得肿瘤血管生成和最终肿瘤生长如何通过调节钙调神经磷酸酶活性和功能来抑制或逆转的机制见解。最后，这些研究也将确定Dscr1是否是抗癌干预的有效靶点。公共卫生相关性：唐氏综合征候选区-1 （Dscr1）基因编码一种阻断肿瘤血管生成，特别是内皮细胞激活的蛋白质。DSCR1负调控vegf - calcalineurin通路，vegf - calcalineurin通路是内皮细胞促进血管生成的重要信号通路。这些研究将确定Dscr1是否是抗癌干预的有效靶点，这可能会导致新的治疗策略来抑制所有癌症的肿瘤血管生成。

DESCRIPTION (provided by applicant): A recently emerging class of anti-cancer therapies has focused on blocking the growth of new blood vessels or angiogenesis, which is necessary to support tumor growth. This proposal is based on a clinical clue provided by a unique population, individuals with Down syndrome, and seeks to define the molecular mechanisms underlying the cancer protection observed in the Down syndrome population. Epidemiological data suggests that a gene(s) present in 3 copies on chromosome 21 exerts a broad anti-cancer effect by controlling some common aspect of tumorigenesis. This proposal focuses on one promising candidate for this activity - the Down syndrome candidate region-1 (Dscr1) gene. The Dscr1 gene encodes a protein that blocks angiogenesis and specifically endothelial cell activation by negatively regulating VEGF-calcineurin signaling. We hypothesize that trisomic expression of Dscr1 in Down Syndrome suppresses tumor growth by attenuating VEGF-calcineurin-NFAT signaling and restricting tumor angiogenesis. In Specific Aim 1, we will determine whether over-expression of DSCR1 is responsible for suppression of tumor growth in Down syndrome by using genetically engineered mouse models recently generated in my lab. In Specific Aim 2 we will examine the role of thrombospondin-1 (TSP-1), a recently identified target in my lab of VEGF-calcineurin-NFAT signaling in endothelial cells, in modulating tumor angiogenesis. We will confirm the mechanism of Tsp-1 regulation by VEGF-calcineurin signaling and determine its role in modulating the pro-angiogenic effects of VEGF. We will also determine the consequences of Tsp-1 loss on VEGF signaling in endothelial cells. In Specific Aim 3, we will determine the differential mechanisms by which DSCR1 and the pharmacologic calcineurin inhibitor cyclosporin A, block calcineurin function using a combination of biochemical and mutational approaches and transplantable tumor models in mice. The experiments proposed will use this clinical insight to derive mechanistic insight into how tumor angiogenesis and ultimately tumor growth can be inhibited or reversed by modulating calcineurin activity and function. Finally these studies will also establish whether Dscr1 is a valid target for anti-cancer intervention. PUBLIC HEALTH RELEVANCE: The Down syndrome candidate region-1 (Dscr1) gene encodes a protein that blocks tumor angiogenesis and specifically endothelial cell activation. DSCR1 negatively regulates the VEGF-calcineurin pathway, an important signaling pathway in endothelial cells to promote angiogenesis. These studies will establish whether Dscr1 is a valid target for anti-cancer intervention which may lead to novel therapeutic strategies for suppressing tumor angiogenesis in all cancers.