This proposal describes a comprehensive five-year training program designed to foster the development of Dr. Bryan D. Kraft, M.D. (Principal Investigator) into an independent physician-scientist. Dr. Kraft completed his residency in Internal Medicine and fellowship in Pulmonary, Allergy, and Critical Care Medicine at Duke University Medical Center where he is now a Medical Instructor. Dr. Kraft?s long term goal is to develop novel therapeutic approaches to the resolution of acute lung injury (ALI) in critically-ill patients. Dr. Kraft?s research focus is mechanisms of lung repair following bacterial pneumonia, a leading cause of death worldwide despite the use of antibiotics. In pursuit of his goal, Dr. Kraft has worked for four years using murine and nonhuman primate (NHP) pneumonia models under the mentorship of his sponsor, Dr. Claude Piantadosi, an expert in ALI and mitochondrial quality control mechanisms. Dr. Piantadosi has a record of successfully mentoring more than 40 junior investigators. The career development program proposed by Dr. Kraft incorporates laboratory training, formal didactics, attendance at scientific conferences, and an advisory committee composed of experts in S-nitrosothiol (SNO) biology and mitochondrial signaling mechanisms. During his Fellowship training, it became apparent that a critical cellular program for lung repair following ALI is mitochondrial biogenesis, the generation of new mitochondrial mass. Preliminary studies presented in this proposal indicate that mitochondrial biogenesis can be activated in lung alveolar type II epithelial (AT2) cells, the progenitor cells of the alveolar region, by pharmacologically augmenting the levels of total lung SNOs. SNO proteins have undergone S-nitrosylation, a post-translational modification whereby NO is transferred to the sulfur moieties of cysteine thiols. Preliminary data indicate that a potential mechanism for these findings is S-nitrosylation (and therefore inactivation) of the protein phosphatases PTEN and PHLPP that de-phosphorylate (de-activate) Akt1, a protein kinase activator of the transcriptional network for mitochondrial biogenesis. The central hypotheses of the proposal are that 1) SNOs activate mitochondrial biogenesis in AT2 cells via phosphatase inhibition leading to increased Akt1 phosphorylation and activation of key downstream repair genes; and 2) SNO-mediated induction of mitochondrial biogenesis will accelerate lung repair following bacterial pneumonia. These hypotheses will be tested with the following Specific Aims: 1) Determine if S-nitrosylation of (a) PTEN and/or (b) PHLPP activate Akt1 and mitochondrial biogenesis in lung AT2 cells; and 2) Determine if pharmacologic SNO augmentation can accelerate resolution of ALI following murine S. aureus pneumonia. This work is expected to yield important insight into why endogenous mechanisms may not be sufficient to resolve severe pneumonia with ALI as well as novel regulatory mechanisms of mitochondrial biogenesis that could be pharmacologically exploited to accelerate pneumonia resolution.

Public Health Relevance

/ PUBLIC HEALTH RELEVANCE Pneumonia is the third leading cause of death worldwide and results in over three million deaths per year. While antibiotics serve to limit the infection, they are not sufficient to promote resolution of severe pneumonia with ALI. The work outlined in this proposal will improve our understanding of pro-survival, pro-resolution signaling pathways in lung epithelial cells and could lead to novel therapies that accelerate the resolution of ALI in patients with severe pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL130557-02
Application #
9412503
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Colombini-Hatch, Sandra
Project Start
2017-01-15
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705