The Role of PMCA2 in Hearing Loss

18.奖学金培训的目标和职业名称(姓氏，名字，中间名)麦卡洛，布伦丹J.机构导师斯坦福大学托马斯·施瓦茨博士华盛顿大学布鲁斯·坦佩尔博士华盛顿大学N/A机构/公司主管/雇主通过这项奖学金获得的知识和经验将使我获得必要的技能，研究与人类疾病相关的详细机制。该奖项的前三年将致力于基础科学研究，调查年龄相关的听力损失和噪音导致的聋哑鼠听力损失。在这段时间里，我打算开发一种科学的方法来处理实验问题，并学习检查这些问题的技术。我将使用的技术包括遗传学、听力功能测量和共聚焦显微镜。我的第四年也是最后一年的奖学金将在诊所度过，作为一名三年级的医学生，为我成为一名医生做准备。总而言之，基础科学研究的深刻性和医学的广博知识将为我成为一名内科科学家做好准备。19.姓名及学位(S)李小龙L 20.耳鼻咽喉及药物学系教席/职级教授研究兴趣/领域听觉信号；神经元多动；听觉神经遗传学；|=：_-__]*_1：IE，]_I，-J：；[e]-Jo]，，‘_.22，描述(不超过所提供的空间)deafwaddler(DFW)小鼠目前是隐性感觉神经性耳聋的模型。然而，杂合子小鼠表现出不同的听力损失，这取决于DFW等位基因的背景和严重程度。致病突变影响编码质膜钙泵PMCA2的Atp2b2基因(Street等人，1998年)。本研究的最终目的是评估DFW杂合子作为年龄相关性听力损失(AHL)和噪声性听力损失(NIHL)的模型。将使用部分功能丧失等位基因(DFW)和功能性零等位基因(DFW 2J)(Penheiter等人，2001；Street等人，1998)。这两个等位基因都保持在CBA/CAJ背景下，这是小鼠听力的“黄金标准”。我们将使用听性脑干反应(ABR)和失真产物耳声发射(DPOAE)测量听力损失。还将对Corti的器官进行显微镜检查，以将组织病理学与功能测量联系起来。另一个目的是通过检测反式杂合子对NIHL的易感性来研究DFW和waltzer(V)基因座之间潜在的遗传交互作用。PHS 416-1(版本，12/98)表第2页bb cc个人非专利申请目录========================================Section End===========================================

18. GOALS FOR FELLOWSHIP TRAINING AND CAREER NAME (Last, first, middle initial) McCullough, Brendan J. INSTITUTION MENTOR Stanford University Dr. Thomas Schwarz University of Washington Dr. Bruce Tempel University of Washington N/A INSTITUTION/COMPANY SUPERVISOR/EMPLOYER The knowledge and experience gained under this fellowship will provide me with the skills necessary to investigate detailed mechanisms associated with human disease. The first three years of this award will be devoted to basic science research investigating age-related hearing loss and noise-induced hearing loss in the deafwaddler mouse. During this time, I intend to develop a scientific approach to experimental questions and learn techniques for examining those questions. Techniques I will use include genetics, functional measurements of hearing and confocal microscopy. My fourth and final year of this fellowship will be spent in the clinic as a third year medical student, preparing me to be a physician. Together, the in-depth nature of basic science research and the broad knowledge of medicine will prepare me for a career as a physician-scientist. 19. NAME AND DEGREE(S) Bruce L Tempel, Phi3 20. POSITION/RANK Professor, Departments of Otolaryngology-HNS and Pharmacology 21. RESEARCH INTERESTS/AREAS Auditory signalling; neuronal hyperactivity; auditory neurogenetics ; |=:_-_]*_1:ie,]_i, -J:;[e]-jo],,.'_.l 22, DESCRIPTION (Do not exceed space provided) The deafwaddler (dfw) mouse is presently a model for recessive sensorineural deafness. Heterozygous mice, however, show variable hearing loss depending on the background and the severity of the dfw allele. The causative mutation affects the Atp2b2 gene encoding the plasma membrane calcium pump PMCA2 (Street, et al., 1998). The ultimate goal of the present study is to evaluate dfw heterozygotes as a model for age-related hearing loss (AHL) and noise-induced hearing loss (NIHL). A partial loss-of-function allele (dfw) and a functional null allele (dfw 2J) will be used (Penheiter et al., 2001; Street et al., 1998). Both alleles are maintained in a CBA/CaJ background, the "gold standard" for hearing in mice. We will measure hearing loss using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements. The organ of Corti will also be examined microscopically in order to correlate histopathology with functional measurements. An additional aim is to investigate a potential genetic interaction between the dfw and waltzer (v) loci by examining the susceptibility to NIHL in trans-heterozygotes. PHS 416-1 (Rev, 12/98) Form Page 2 BB cc Individual NRSA Application Table of Contents ========================================Section End===========================================