Role of microRNA in kidney development and pathogenesis of PKD

描述（由申请人提供）： 该提案描述了一个为期5年的培训计划，用于发展实验室医学的学术生涯。主要研究者（PI）已在西北大学完成了内科住院医师培训，随后在UT西南大学获得了临床肾脏病学奖学金，并在UT西南大学获得了NIH赞助的肾脏病学博士后奖学金（2005-08）。博士彼得Igarashi，医学博士，教授和主任，肾脏科，UT西南，将指导PI在这个奖项的过程中。五十岚博士是PKD领域的专家，过去曾成功指导过许多研究员和研究生。博士埃里克奥尔森，博士，教授和分子生物学，UT西南椅子也将导师PI。Olson博士是世界著名的研究人员，也是micro-RNAs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。 该研究将重点阐明micro-RNAs在肾脏发育和多囊肾疾病中的作用。我们和其他人最近表明，早期新生小鼠肾脏是一个囊肿倾向的状态，由于高增殖率和基因表达谱的发展肾脏。另一方面，由于成熟肾脏的低增殖率和基因表达谱，成人肾脏是囊肿抗性状态。在这个建议中，我们将确定微RNA表达的变化是否是新生肾和成熟肾之间观察到的基因表达变化和增殖下降的基础。此外，我们将研究是否在PKD小鼠模型中观察到异常的micro-RNA表达。这些研究将在UT西南，这提供了一个理想的环境，由于建立教师与不同的研究兴趣和专业知识的存在，医生科学家的发展进行。PI将不受限制地访问UT西南奥布莱恩肾脏中心核心提供的资源。PI将花费80%的时间进行研究相关活动，20%的时间负责临床和培训。一个咨询委员会将监督这项建议的进展。 公共卫生相关性：目前尚无有效的PKD治疗方法。我们的研究结果可能揭示了新的遗传因子称为microRNA在PKD小鼠中异常表达。最近，microRNA表达的调节已被证明可以成功降低血清胆固醇水平。我们的研究将使用类似的microRNA调节来治疗小鼠中的PKD。这些治疗策略最终可以应用于PKD患者。

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.