PROJECT SUMMARY/ABSTRACTCANDIDATE: Dr. Wollmans career objective is to establish an independent research program investigating theinfluence of nicotine withdrawal on oxygen sensing. The research and career development plans have beencarefully designed to provide the necessary skills for Dr. Wollman to establish a novel independent line ofresearch and include the following objectives: 1) to gain further expertise in research methodology andtechniques 2) develop teaching and mentoring skills and 3) to develop grant writing skills and further academicleadership skills. ENVIRONMENT: Primary mentor Dr. Fregosi is an expert in studying breathing both in vivoand in vitro and will provide technical guidance for Aim 1 experiments during the K99 phase. Mentors Dr.Prabhakar is an expert in carotid sinus nerve recordings and patch clamp from carotid body glomus cells andDr. Oweiss is an expert in vivo gCaMP imaging and will provide extensive training to Dr. Wollman during theK99 phase. Both mentors along with the rest of the assembled advisory committee will help to ensure Dr.Wollmans success with this proposal. With the exception of hands on training with Drs. Prabhakar in Chicagoand Oweiss in Florida all of the work proposed here will be carried out in the Fregosi laboratory. Dr. Fregosi hasNIH funding and the resources needed to support Dr. Wollman during the training phase of the research project.The University of Arizona College of Medicine is an ideal setting for the mentored phase of this proposal due tothe outstanding faculty mentors and facilities available. RESEARCH: My overarching hypothesis is that nicotinewithdrawal alters the carotid body and neurons in the nucleus tractus solitarius (NTS) key neural structures thatare involved in oxygen sensing. Preliminary data shows that chronic nicotine exposure has no effect on theventilatory response to hypoxia however rats show a blunted response to hypoxia after 48 hours of nicotinewithdrawal. To build on these novel preliminary data I have designed the following specific aims. Aim 1: Totest the effects of nicotine withdrawal on the ventilatory response to 10 12 or 15% hypoxia and to test the abilityfor an acute dose of nicotine to rescue this response. Aim 2: To test the effects of nicotine withdrawal on oxygensensing in the carotid body NTS neuron activation and the respiratory motor output from the phrenic nerve invivo. Aim 3: To test the effects of nicotine withdrawal on nicotinic acetylcholine receptor function in carotid bodyglomus cells and NTS neurons in vitro. This work will be carried out using plethysmography a uniquecombination of in vivo calcium imaging using fiber photometry and concurrent phrenic nerve recordings andwhole cell patch clamp of glomus cells in excised carotid bodies and NTS neurons in a brainstem slice. Theproposed training plan will allow Dr. Wollman to learn new experimental techniques successfully complete theproposed research and transition to an independent extramurally-funded tenure-track position at a top-tier (R1)research institution.