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集中于阻断新血管或血管生成的生长，这是支持肿瘤生长所必需的。 这项建议是基于一个独特的人群，唐氏综合症个体提供的临床线索，并试图定义唐氏综合症人群中观察到的癌症保护的分子机制。 流行病学数据表明，存在于21号染色体上的3个拷贝的基因通过控制肿瘤发生的一些共同方面而发挥广泛的抗癌作用。 这项建议集中在一个有希望的候选人，这种活动-唐氏综合征候选区域-1（DRD 1）基因。 DAP 1基因编码一种蛋白质，通过负调节VEGF-钙调磷酸酶信号传导阻断血管生成，特别是内皮细胞活化。 我们推测唐氏综合征中DAP 1的三体表达通过减弱VEGF-钙调神经磷酸酶-NFAT信号传导和限制肿瘤血管生成来抑制肿瘤生长。 在具体目标1中，我们将通过使用我实验室最近生成的基因工程小鼠模型来确定DSCR 1的过度表达是否负责抑制唐氏综合征中的肿瘤生长。 在具体目标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是我实验室最近确定的内皮细胞VEGF-钙调神经磷酸酶-NFAT信号转导的靶点。 我们将确认Tsp-1通过VEGF-钙调神经磷酸酶信号调节的机制，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Tsp-1缺失对内皮细胞中VEGF信号传导的影响。 在具体目标3中，我们将确定DSCR 1和药理学钙调磷酸酶抑制剂环孢素A的差异机制，使用生物化学和突变方法和小鼠可移植肿瘤模型的组合阻断钙调磷酸酶功能。 提出的实验将使用这种临床见解，以获得如何通过调节钙调磷酸酶活性和功能来抑制或逆转肿瘤血管生成和最终肿瘤生长的机制见解。 最后，这些研究还将确定DIFF 1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（DRD 1）基因编码一种蛋白质，可阻断肿瘤血管生成，特别是内皮细胞活化。 DSCR 1负调节VEGF-钙调磷酸酶通路，这是内皮细胞中促进血管生成的重要信号通路。 这些研究将确定DAP 1是否是抗癌干预的有效靶点，这可能导致抑制所有癌症中肿瘤血管生成的新治疗策略。

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.