The Lymphangioleiomyomatosis (LAM)Genome Atlas

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题15-OD（ORR）-101*“罕见疾病预防、早期检测和治疗的试点项目。“淋巴管平滑肌瘤病（LAM）是一种影响年轻女性的常见致命的罕见疾病，其病理特征是肺部弥漫性浸润，伴异常平滑肌细胞和肺实质囊性变性。LAM作为一种孤立的疾病（散发性LAM）以及结节性硬化症（TSC，TSC-LAM）的女性发生。肾血管平滑肌脂肪瘤见于约60%的散发性LAM患者。血管平滑肌脂肪瘤是良性间叶肿瘤，由异常厚壁血管、平滑肌细胞和脂肪细胞组成。LAM和血管平滑肌脂肪瘤的平滑肌细胞惊人地相似，表达多种黑素细胞蛋白，导致假设它们来自神经嵴祖细胞。 该建议的第一个关键目标是分别确定血管平滑肌脂肪瘤和LAM细胞的基因和microRNA表达谱，以帮助确定其起源细胞和对激素治疗的可能反应。第二个关键目标是确定散发性LAM中TSC 1和TSC 2的体细胞点突变和基因组突变的频率，并确定Rheb中的激活突变是否与散发性LAM相关。我们的第三个关键目标是确定与LAM和血管平滑肌脂肪瘤相关的其他遗传事件。基于与其他肿瘤过程的类比，我们期望在其他基因中发现突变，从而为发病机制和治疗提供见解。我们将使用三种并行的方法。首先，我们将使用高分辨率全基因组SNP方法来定义染色体丢失或获得的区域。其次，我们将使用Oncomap在400多个癌基因中寻找特定的突变。第三，我们将直接测序2,000个肿瘤相关基因的所有外显子，全面筛查其他突变。因此，该提议将解决LAM发病机制和生物学中的一些最关键的问题。首先，TSC 1或TSC 2突变与散发性LAM之间的关联有多广泛？第二，哪些其他突变或基因组事件可以作为治疗靶点参与LAM发病机制？第三，LAM细胞的表达谱揭示了LAM的细胞起源、雌激素的作用和肺破坏的机制？我们坚信，这些问题的答案将阐明与LAM以及其他相关疾病相关的细胞通路，并将为这种经常进行性和致命性疾病的治疗干预提供机会。 公共卫生相关性：淋巴管平滑肌瘤病（LAM）是一种罕见的疾病，几乎只影响妇女，肺移植是唯一被证明的治疗方法。在这个提议中，我们将定义LAM细胞的表达特征，使其谱系解剖，并定义发生在LAM中的基因组改变。这些研究将深入了解这种疾病是如何发展的，并使新的治疗方法能够预防LAM女性的肺破坏。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science, and specific Challenge Topic 15-OD(ORDR)-101* "Pilot projects for prevention, early detection and treatment of rare diseases." Lymphangioleiomyomatosis (LAM) is an often-fatal rare disease affecting young women, characterized pathologically by a diffuse infiltration of the lungs with abnormal smooth muscle cells and cystic degeneration of the lung parenchyma. LAM occurs as an isolated disorder (sporadic LAM) as well as in women with tuberous sclerosis complex (TSC, TSC-LAM). Renal angiomyolipomas are found in ~60% of sporadic LAM patients. Angiomyolipomas are benign mesenchymal tumors consisting of abnormal thick-walled vessels, smooth muscle cells, and fat cells. The smooth muscle cells of LAM and angiomyolipomas are strikingly similar, expressing multiple melanocytic proteins, leading to the hypothesis that they are derived from a neural crest progenitor cell. The first key objective of this proposal is to separately define the gene and microRNA expression profiles of angiomyolipomas and LAM cells, to help define their cell-of-origin and possible response to hormonal therapies.The second key objective is to determine the frequency of somatic point and genomic mutations in TSC1 and TSC2 in sporadic LAM, and to determine whether activating mutations in Rheb are associated with sporadic LAM. Our third key objective is to identify other genetic events associated with LAM and angiomyolipomas. Based on analogy to other neoplastic processes, we expect to find mutations in other genes, providing insight into pathogenesis and therapy. We will use three parallel approaches. First, we will define regions of chromosomal loss or gain using a high resolution genome-wide SNP approach. Second, we will seek specific mutations in more than 400 oncogenes using Oncomap. Third, we will directly sequence all exons of 2,000 tumor-associated genes to comprehensively screen for other mutations. Thus, this proposal will address some of the most critical questions in LAM pathogenesis and biology. First, how broad is the association between TSC1 or TSC2 mutations and sporadic LAM? Second, what other mutations or genomic events that can be therapeutically targeted participate in LAM pathogenesis? Third, what does the expression profile of LAM cells reveal about the cell-of-origin, role of estrogen, and mechanisms of lung destruction in LAM? We strongly believe that answers to these questions will elucidate cellular pathways relevant to LAM, as well as other related disorders, and will also provide the opportunity for therapeutic intervention in this all-too-often progressive and fatal disorder. PUBLIC HEALTH RELEVANCE: Lymphangioleiomyomatosis (LAM) is a rare disease affecting almost exclusively women, for which lung transplantation is the only proven treatment. In this proposal we will define the expression characteristics of LAM cells, enabling dissection of its lineage, and define the genomic alterations that occur in LAM. These studies will provide insight into how this disease develops, and enable novel treatment approaches to prevent lung destruction in women with LAM.