PROJECT SUMMARY/ABSTRACT Christopher Brown MD, PhD is an Instructor of Medicine in the division of infectious diseases at Weill- Cornell Medical College in New York City. His research interests focus on defining the biology of transmission in Mycobacterium tuberculosis. This five-year training grant outlines technical, research and professionalism goals needed to launch an independent academic career. Dr. Brown has extensive research training as an organic chemist and chemical biologist from his doctoral work in the laboratory of Laura L. Kiessling. This proposal expands into the fields of microbiology, metabolomics and regulated gene expression. Utilizing a combination of these disciplines is a powerful method for the molecular interrogation of biological systems. Mtb transmission biology is a field of substantial opportunity for discovery. Development of a transmission blocking therapy would have a profound impact on global health and mortality. The research goal of this proposal is to identify bacterially-encoded determinants that favor successful transmission by imparting survival in air. The PI will expose laboratory and clinical strains of Mtb to air-drying stress and document the effects on metabolism and cellular integrity. Hypotheses regarding the essentiality of metabolic pathways for survival will be tested using CRISPRi (clustered regularly interspersed short palindromic repeat interference) gene silencing.