PROJECT SUMMARY / ABSTRACT Tuberculosis (TB) is the leading cause of infectious disease death globally, and accounts for 4 out of 10 deaths in HIV-infected individuals. Although progress has been made in decreasing incidence and mortality from TB, the current trends are woefully insufficient to achieve the WHO End TB goal of fewer than 10 TB cases per 100,000 population by 2035. Innovative research to develop new diagnostic, therapeutic and prevention tools are critically needed. Thus, training the next generation of scientists with expertise to carry out translational studies in TB and TB/HIV co-infection in high burden settings is an important priority. The goal of this K24 competitive renewal is to continue to mentor promising young investigators in clinical and translational patient- oriented research in TB, HIV and Global Health. My current K24 has been very successful in supporting mentorship for 33 trainees, and in allowing me to expand my research program substantially to include molecular epidemiology, TB immunology and clinical trials. The current K24 supported 36 publications, including 26 with a mentee as first author. Mentees were also successful in submitting extramural grants, including NIH K career development awards and making the transition from K awards to their first R01 grants. In this competitive renewal, I will expand my own training to: 1) understand how human genetics and epigenetics can elucidate mechanisms underlying susceptibility and resistance to Mtb infection; 2) gain further expertise in spatial epidemiology and spatial statistics to inform studies of TB transmission; and 3) enhance my mentorship and leadership skills to prepare my trainees for careers in patient-oriented research. This additional training will enhance my mentorship of trainees participating in our ongoing R01 studies examining: the role of casual contact in TB transmission; and host genetic polymorphisms associated with resistance to Mtb infection. The K24 continuation will also facilitate a pilot epigenetic study investigating two novel specific research aims: 1) to assess candidate DNA methylation sites for association with resistance to Mtb infection; and 2) to identify epigenetic predictors of resistance to Mtb infection using an epigenome-wide approach. The research from my ongoing R01 studies and the proposed new pilot study will generate novel insights into factors associated with TB transmission and susceptibility to Mtb infection to inform the development of epidemiologic interventions and preventive therapeutics to reduce the number of new Mtb infections. Further, the data and specimens generated will provide numerous training opportunities for my mentees to develop their own career development projects.

PROJECT NARRATIVE Tuberculosis is the leading infectious disease cause of death worldwide and accounts for 4 out of every 10 death in HIV-infected individuals. Neel Gandhi, M.D., is a physician-scientist at Emory University dedicated to patient-oriented research in TB, HIV and global health. Continuation of this K24 award will provide the needed protected time for Dr. Gandhi to provide mentorship to young investigators pursuing these fields and to expand his research program in the emerging areas of genetics, epigenetics, spatial epidemiology and spatial statistics.