Kynurenine: a potential link between age-related decreases in bone mass and kidney function

项目摘要 骨质疏松症是一个主要的公共卫生问题，影响着4400万美国人，估计耗资170亿美元 2001年尤其是老年人的骨折可导致显著的发病率和死亡率。理解 本申请的重点是在衰老过程中引起骨损失的肾机制。肾脏负责 维生素D的合成，并有助于控制钙和磷酸盐的水平。骨产生的FGF 23 和它的共同受体，Eklotho有助于调节这些过程，以及这些因素或其任何一种的失调。 下游信号可导致骨丢失。衰老也会损害肾功能，这也可能导致 与衰老有关的骨质流失。然而，骨骼是否会影响肾功能尚不清楚。 色氨酸是人体必需的九种氨基酸之一，是一种有效的抗氧化剂，但其含量会随着年龄的增长而下降; 然而，其稳定氧化代谢物犬尿氨酸随着年龄增长而增加， 增殖我们实验室的工作表明，小鼠中的犬尿氨酸喂养导致骨质流失。我们 中心假设是增加的犬尿氨酸水平诱导衰老表型， 通过FGF 23/αKlotho途径导致肾功能障碍。 博士Irsik将在信号专家Wendy Bollag博士的指导下进行这些实验 转导，并已连续VA Merit资助了十几年。为了在衰老中获得知识 研究，她将努力在老年学证书，并与她的职业生涯的成员合作 咨询委员会，以获得在老化研究的实验设计的专业知识。Isales博士将提供以下方面的专业知识 老化和骨骼研究，而Carbone博士是退伍军人骨骼问题的专家，Dong博士被公认为 他在急性肾损伤方面的研究Irsik博士将通过学习表演来扩展她目前的研究技能 DXA、骨密度CT和骨组织学检查，通过医生、Bollag和Isales的合作进行。董博士将提供 在她的肾脏研究的援助，和Carbone博士将教她如何与大型数据集，通过 退伍军人事务部她将每周与骨组的所有成员互动，包括临床医生和基础医生。 来自多个部门和学科的科学家，每年两次展示自己的研究成果。她将介绍 她的研究在每年至少两次国际会议（ASBMR，生物学，GSA或实验生物学）。 她向独立的过渡将得到Bollag博士的指导，他指导了许多学员 在学术研究中取得成功她提供了一个成功的女博士科学家的观点 而Isales博士是一名临床医生，多年来一直倡导少数民族研究人员的代表性不足。 这两名调查人员有着大约30年的成功合作记录， 将有助于确保Irsik博士获得必要的指导，为独立的 研究老龄化的职业生涯。该CDA 2奖将用于获得必要的初步数据， 申请她自己的VA优异奖，从而使她获得她的第一个终身教职。

Project Summary Osteoporosis is a major public health problem affecting 44 million Americans and costing an estimated $17 billion in 2001. Bone fractures in the elderly in particular can result in significant morbidity and mortality. Understanding the renal mechanisms that underlie bone loss in aging is the focus of this application. The kidney is responsible for Vitamin D synthesis and contributes to the control of calcium and phosphate levels. Bone-produced FGF23 and its co-receptor, Klotho help to regulate these processes, and dysregulation in these factors or any of their downstream signals can lead to bone loss. Aging also impairs kidney function which may also contribute to aging-related bone loss. However, whether the bone can affect kidney function is not known. Tryptophan, one of nine essential amino acids, is a potent anti-oxidant but its levels decrease with aging; however, its stable oxidized metabolite, kynurenine increases with age and inhibits bone marrow stem cell proliferation. Work from our laboratory has shown that kynurenine feeding in mice results in bone loss. Our central hypothesis is that augmented kynurenine levels induce an aged phenotype resulting in both bone loss and kidney dysfunction through the FGF23/αKlotho pathway. Dr. Irsik will conduct these experiments under the mentorship of Dr. Wendy Bollag, who has expertise in signal transduction and has been continuously VA Merit-funded for a dozen years. In order to gain knowledge in aging research, she will work towards a certificate in gerontology and collaborate with the members of her career advisory committee to gain expertise in experimental design in aging studies. Dr. Isales will provide expertise in aging and bone research while Dr. Carbone is an expert in bone issues in veterans and Dr. Dong is recognized for his research in acute kidney injury. Dr. Irsik will expand her current research skills by learning to perform DXA, CT and bone histology through the collaborative efforts of Drs, Bollag and Isales. Dr. Dong will provide assistance in her renal studies, and Dr. Carbone will teach her how to work with large datasets available through the VA. She will interact weekly with all the members of the Bone Group, comprised of both clinicians and basic scientists from multiple departments and disciplines, presenting her own research twice a year. She will present her research at a minimum of two international meetings per year (ASBMR, ASN, GSA or Experimental Biology). Her transition to independence will be enhanced by the mentorship of Dr. Bollag, who has guided many trainees to successful careers in academic research. She provides the perspective of a successful woman PhD scientist while Dr. Isales is a clinician who has advocated for under-represented minority researchers for many years. Together these two investigators, who have a successful track record of collaborating for approximately 30 years, will help to ensure that Dr. Irsik receives the mentoring necessary to be well-prepared for an independent research career in aging. This CDA2 award will be leveraged to obtain the preliminary data necessary for her to apply for her own VA Merit Award, thereby allowing her to obtain her first tenure-track faculty position.