Molecular Genetics

项目总结（见说明）： 项目1：分子遗传学 慢性淋巴细胞白血病（CLL）是一种影响50岁以上个体的不治之症，是西方世界最常见的白血病。目前，治疗CLL的临床方法是“等待和观察”，因为在大多数情况下，该疾病是无痛的，通常持续很长一段时间，尽管随着时间的推移，它可能转化为侵袭性疾病。因此，用积极的化疗/免疫疗法治疗可能长时间保持惰性的疾病可能适得其反。 相反，涉及约20-30%患者的侵袭性形式的CLL是一种预后不良的恶性疾病，应及时积极治疗。 在过去的几年里，在这项资助的支持下，以及与其他项目研究人员的互动和合作，我们发现了导致慢性淋巴细胞白血病惰性和侵略性形式的根本遗传变化。是的也能够开发攻击性和惰性形式的CLL的小鼠模型。最近，我们比较了从CLL患者获得的样品中的microRNA表达谱，这些患者多年来一直保持惰性，从CLL患者获得的样品是惰性的，但随着时间的推移变得具有侵略性，我们已经确定了与恶性进展相关的microRNA表达的特定变化。 在这次更新申请中，我们打算通过以下目的来揭示将惰性疾病转化为侵袭性疾病的根本变化： 目的#1检测CLL进展过程中全基因组microRNA的改变 目的#2研究由改变的microRNA控制的分子网络 目的#3在CLL进展过程中促进microRNA失调的因素的鉴定我们还计划利用我们在该资助支持下开发的小鼠模型来解开肿瘤进展中涉及的机制，从而促进对人类CLL进展的理解。

PROJECT SUMMARY (See instructions): PROJECT 1 : Molecular Genetics Chronic lymphocytic leukemia (CLL), an incurable disease that affects individuals over 50 years of age, is the most common leukemia in the Western World. At present, the clinical approach to the treatment of CLL is "wait and watch" because in most cases the disease is indolent, often for long periods of time, although with time it may transform into an aggressive disease. Thus, it may be counterproductive to treat a disease that may remain indolent for long periods of time with aggressive chemo/immunotherapy. On the contrary, the aggressive form of CLL, that involves approximately 20-30% of patients, is a malignant disease with poor prognosis that should be treated promptly and aggressively. During the past few years, with the support of this grant and of interactions and collaborations with investigators of the other projects, we have discovered the fundamental genetic changes responsible for the indolent and aggressive forms of CLL. We were. also able to develop mouse models for both the aggressive and indolent forms of CLL. Recently we have compared the microRNA expression profiles in samples obtained from CLL patients that have remained indolent for many years, to samples obtained from CLL patients that were indolent but became aggressive with time and we have identified specific changes in microRNA expression that correlate with the malignant progression. In this renewal application, we intend unravel the fundamental changes that convert an indolent to an aggressive disease by the following aims: AIM #1 Detection of the genome-wide microRNA alterations during the progression of CLL AIM #2 Studies of the molecular networks controlled by the altered microRNAs AIM #3 Identification of the factors promoting microRNAs dysregulation during the progression of CLL We also plan to exploit the mouse models we have developed with this grant support to unravel the mechanisms involved in tumor progression, thus facilitating an understanding of the progression of human CLL.