PROJECT SUMMARY / ABSTRACT CANDIDATE: Matthew C. Babcock, Ph.D. is an Assistant Professor at the University of Colorado Anschutz Medical Campus (CU-AMC). Dr. Babcock aims to study the neural and renal contributions to hypertension with androgen deprivation therapy (ADT). He has developed preliminary data indicating that 1) men with lower testosterone concentrations have reduced baroreflex sensitivity compared to men with higher testosterone concentrations; and 2) baroreflex sensitivity in these individuals is correlated with circulating concentrations of the proinflammatory cytokine interleukin-6. In this proposal, he will translate these data by comprehensively assessing neural control of blood pressure in men who undergo ADT, and extend his observations to include renal control of blood pressure. The central hypothesis is that ADT increases inflammation and thereby reduces baroreflex sensitivity, increases sympathetic reactivity, and increases renovascular resistance. CAREER DEVELOPMENT PLAN: Dr. Babcock proposes to enhance his career development by: 1) acquiring new skills in the assessment of renal plasma flow, assessment of renal function biomarkers, and assessment of pro- inflammatory cytokines; 2) Advanced training renal diseases and physiology; 3) Working with a clinical population by recruiting men diagnosed with prostate cancer and studying them while they undergo ADT under the guidance of Dr. Elizabeth Kessler, a medical oncologist who specializes in prostate cancer; and 4) Refining his professional skills through formal course work, attendance and presentations at weekly Scientific Advancement and Grand Rounds, and at national scientific meetings. ENVIRONMENT: Dr. Babcock will train in an outstanding research environment supported by a multi-disciplinary team of mentors. The primary mentor, Dr. Moreau, is an NIA- funded professor at CU-AMC with a record of successful mentorship. She is an expert in the role of sex hormones and inflammation on cardiovascular function. She has extensive experience in utilizing the gonadal suppression study design proposed in the current study. Co-Mentor Dr. William Cornwell, III is also at CU-AMC and an expert in autonomic control of the circulation. Co-Mentor Dr. Jessica Kendrick and advisor Dr. Petter Bjornstad are also at CU-AMC and experts in studying renal function. Advisor Dr. Kessler is an expert in prostate cancer and ADT. Advisor Drs. Joyner and Farquhar are experts in autonomic function and the exercise pressor reflex. RESEARCH: ADT is a mainstay in the management of prostate cancer and the impressive survival rates among with men diagnosed with prostate cancer is largely attributed to the effectiveness of ADT. However, ADT increases the likelihood of developing hypertension and, accordingly, prostate cancer survivors who were treated with ADT are more likely to die early from cardiovascular diseases compared to men treated without the use of ADT. There is a critical need to elucidate the mechanisms underlying the increased cardiovascular disease risk in these patients to improve the lives of prostate cancer survivors.

PROJECT NARRATIVE Prostate cancer is the most common non-skin cancer among men and androgen deprivation therapy is an effective mainstay treatment that has greatly reduced mortality related to primary cancer. However, men who undergo androgen deprivation therapy are more likely to develop hypertension and die from cardiovascular diseases than men who are treated for prostate cancer without the use of androgen deprivation therapy. Therefore, I am seeking to determine the neural and renal contributions to hypertension in men who undergo androgen deprivation therapy, as well as the mechanistic influence of inflammation on these outcomes.