Role of microRNA in kidney development and pathogenesis of PKD

描述(由申请人提供)： 这项建议描述了一项为期5年的培训计划，以发展实验室医学的学术生涯。首席调查员(PI)在西北大学完成了内科住院医师培训，随后在德克萨斯大学西南分校获得了临床肾病奖学金，并在德克萨斯大学西南分校肾脏病学部获得了NIH赞助的博士后奖学金(2005-08)。Peter Igarashi博士，医学博士，德克萨斯大学西南分校肾病科教授兼主任，将在此奖项过程中指导PI。Igarashi博士是PKD领域的专家，过去曾成功指导过许多研究员和研究生。德克萨斯大学西南分校分子生物学教授兼主任、博士埃里克·奥尔森博士也将指导PI。奥尔森博士是世界知名的研究人员，也是微型核糖核酸领域的专家。奥尔森博士将在颁奖过程中提供指导和建议。奥尔森博士的实验室小组将与PI共享试剂和资源。 这项研究将集中于阐明microRNAs在肾脏发育和多囊肾病中的作用。我们和其他人最近表明，由于发育中的肾脏的高增殖率和基因表达谱，早期新生小鼠的肾脏是一种易于囊性生长的状态。另一方面，由于成熟肾脏的低增殖率和基因表达谱，成人肾脏是一种囊性抵抗状态。在这项建议中，我们将确定微小RNA表达的变化是否是新生儿肾脏和成熟肾脏之间观察到的基因表达变化和增殖下降的基础。此外，我们还将研究在小鼠PKD模型中是否观察到微小RNA的异常表达。这些研究将在德克萨斯大学西南分校进行，由于拥有具有不同研究兴趣和专业知识的知名教员，该校为内科科学家的发展提供了理想的环境。PI将不受限制地访问德克萨斯大学西南部奥布莱恩肾脏中心核心提供的资源。PI将花费80%的时间执行与研究相关的活动，20%的时间用于临床和培训职责。一个咨询委员会将监督这项提案的进展情况。 与公共卫生相关：目前尚无有效的治疗PKD的方法。我们的研究结果可能表明，新的遗传因素称为microRNAs在PKD小鼠中异常表达。最近，微RNA表达的调节已被证明成功地降低了血清胆固醇水平。我们的研究将使用类似的microRNAs调制来治疗小鼠的PKD。这些治疗策略最终可以应用于患有PKD的人类。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Laboratory Medicine. The principle investigator (PI) has completed a structured residency training in Internal Medicine at Northwestern University followed by clinical Nephrology fellowship at UT Southwestern and a NIH sponsored post doctoral fellowship in the Division of Nephrology at UT Southwestern (2005-08). Dr Peter Igarashi, MD, Professor and Chief, Division of Nephrology, UT Southwestern, will mentor the PI during the course of this award. Dr Igarashi is an expert in the field of PKD and has successfully mentored numerous fellows and graduate students in the past. Dr Eric Olson, PhD, Professor and Chair of Molecular Biology, UT Southwestern will also mentor the PI. Dr Olson is a world renowned researcher and a expert in the field of micro-RNAs. Dr Olson will provide guidance and advice during the course of this award. Dr Olson's lab group will share reagents and resources with the PI. The research will focus on elucidating the role of micro-RNAs in kidney development and polycystic kidney disease. We and others have recently shown that early neonatal mouse kidney is a cyst prone state due to high rates of proliferation and gene expression profile of a developing kidney. On the other hand, adult kidney is a cyst resistant state due to low rates of proliferation and gene expression profile of a mature kidney. In this proposal we will determine whether changes in micro-RNA expression underlies the change in gene expression and decline in proliferation observed between the neonatal kidney and mature kidney. Furthermore, we will study whether aberrant micro-RNA expression is observed in murine models of PKD. These studies will be conducted at UT Southwestern, which provides an ideal setting for development of physician-scientists due to the presence of established faculty with diverse research interests and expertise. The PI will have unrestricted access to the resources provided by UT Southwestern O'Brien Kidney center core. The PI will spend 80% of time performing research related activities and 20% of time in clinical and training responsibilites. An advisory committee will oversee the progress of this proposal. PUBLIC HEALTH RELEVANCE: Currently no effective treatment for PKD exists. Results of our studies may reveal that novel genetic factors called microRNAs are abnormally expressed in mice with PKD. Recently, modulation of microRNA expression has been shown to successfully decrease serum cholesterol levels. Our studies will use similar modulation of microRNAs to treat PKD in mice. These treatment strategy can be eventually applied to humans with PKD.