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Principal Investigator: Joseph Charles Cooley
Organization: NATIONAL JEWISH HEALTH
Fiscal Year: 2024
Award: $156,816
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
This proposal describes a five-year project through which Dr. Joseph Cooley will develop the skills and
knowledge necessary to transition into an independent basic and translational physician-scientist. He will receive
mentorship from a primary mentor, several advisors and collaborators from National Jewish Health and the
University of Colorado. His long-term career goal is to help patients with fibrotic lung diseases by uncovering
mechanisms of progressive pulmonary fibrosis (PPF) and developing therapeutic strategies to halt or reverse
fibrosis. This proposal explores how interleukin-6 (IL-6) promotes apoptosis resistance in fibroblasts by
increasing expression of the anti-apoptotic protein BCL-2, and how this IL-6-BCL-2 axis can be targeted
therapeutically. It is directly relevant to the NHLBI given its applicability to all progressive fibrosing interstitial lung
diseases (ILDs). Candidate: Joseph Cooley, DO is board certified in Internal, Pulmonary, and Critical Care
Medicine. He is an Instructor at National Jewish Health in Denver, CO who clinically specializes in ILD and
performs rigorous basic and translational scientific investigations related to pulmonary fibrosis as a physician-
scientist. Training: Dr. Cooley has created an extensive career development plan that builds on his prior
mentored research during medical school, residency, and fellowship training. His multi-faceted career
development plan utilizes formal classwork, conferences, seminars, workshops, small and large group
collaborative meetings, and on-on-one training to develop and expand his skills and knowledge of 1) biologic
concepts related to mechanisms of cell death, biostatistics, genetics and genomics, and lung injury, repair and
fibrosis, 2) laboratory techniques, 3) scientific writing, 4) rigorous experimental design, 5) data interpretation, 6)
oral presentation, and 7) leadership, mentorship and laboratory management. Mentor/Environment: Dr.
Cooley’s primary mentor is Dr. Elizabeth Redente, PhD whose laboratory has a history of producing high-impact
research regarding fibroblasts behavior during lung injury, repair and fibrosis. Dr. Cooley has assembled a team
of mentors and collaborators that are experts in pertinent aspects of the project including advanced genomic
analysis techniques (Dr. Gerber), cutting edge gene transfer techniques using viral vectors (Dr. Bridges),
genetics and genomics of pulmonary fibrosis (Dr. Schwartz), and IL-6 signaling across diverse disease states
(Dr. Rincon). All proposed activities will be performed at National Jewish Health, a highly collaborative top-ranked
research institution. Research Project: The primary objective of this proposal is to determine if fibroblast BCL-
2 dependent apoptosis resistance is driven by sustained IL-6 signaling in PPF, and if this IL-6-BCL-2 axis can
be targeted therapeutically to treat PPF. We will use in vitro cell culture and precision cut lung slices from humans
and mice, and in vivo mouse models to determine 1) the effects of IL-6 on BCL-2 expression in fibroblasts during
PPF, 2) the causal role of IL-6 in driving PPF and 3) ability of IL-6 signaling inhibition or genetic knockout to
reduce BCL-2 expression in fibroblasts, induce fibroblast apoptosis and reverse established PPF.
Terms: <Acceleration><Address><Adeno-Associated Viruses><Apoptosis><Apoptosis Pathway><Apoptotic><Autocrine Systems><Automobile Driving><Award><B cell differentiation factor><B cell lymphoma 2><B cell stimulating factor 2><B-Cell CLL/Lymphoma 2 Gene><B-Cell Chronic Lymphocytic Leukemia Associated Oncogene><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-cell Leukemia 1><B-cell lymphoma/leukemia-2><BCDF><BCL><BCL1 Oncogene><BCL2><BCL2 gene><BSF-2><BSF2><Basal Transcription Factor><Basal transcription factor genes><Bcl-2><Behavior><Biological><Biometrics><Biometry><Biostatistics><Bleo><Bleomycin><Board Certification><Cell Communication and Signaling><Cell Culture Techniques><Cell Death><Cell Signaling><Cell-Extracellular Matrix><Clinical><Clinical Treatment Moab><Collaborations><Colorado><Contracting Opportunities><Contracts><Critical Care><Data Analyses><Data Analysis><Dependoparvovirus><Dependovirus><Deposit><Deposition><Development><Development Plans><Disease><Disorder><Distal><Doctor of Philosophy><Dose><Drugs><ECM><Educational workshop><Effector Cell><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Experimental Designs><Extracellular Matrix><Family member><Fellowship><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Gene Transfer><Gene Transfer Techniques><General Transcription Factor Gene><General Transcription Factors><Genetic><Genomics><Goals><Granulation Tissue><HPGF><Health><Hepatocyte-Stimulating Factor><History><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL-6 inhibitor><IL6 Protein><IL6 inhibitor><In Vitro><Inflammation><Institution><Interleukin-6><Interleukin-6 inhibitor><Interruption><Interstitial Lung Diseases><Intracellular Communication and Signaling><Investigation><Investigators><Jewish><Judaism><Knock-out><Knockout><Knowledge><Laboratories><Leadership><Lung><Lung Respiratory System><Lung Tissue Fibrosis><Lung damage><MGI-2><Mediating><Medication><Medicine><Mentors><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Murine><Mus><Myeloid Differentiation-Inducing Protein><Myofibroblast><NHLBI><National Heart, Lung, and Blood Institute><Oral><Patients><Pattern><Ph.D.><PhD><Pharmaceutical Preparations><Phenotype><Physicians><Plasmacytoma Growth Factor><Process><Programmed Cell Death><Proteins><Publications><Pulmonary Fibrosis><R-Series Research Projects><R01 Mechanism><R01 Program><Recording of previous events><Reporter><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Residencies><Resistance><Resistance development><Resistant development><Resolution><Role><STAT3><STAT3 gene><Scientific Publication><Scientist><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Techniques><Testing><Therapeutic><Training><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation><Transgenesis><Universities><Viral Vector><Work><Workshop><Wound Repair><Writing><adeno associated virus group><autocrine><bcl-2 Genes><biologic><biological signal transduction><career><career development><ced9 homolog><cell culture><cell cultures><clinical relevance><clinically relevant><conference><convention><data interpretation><developing resistance><developmental><diffuse interstitial pulmonary fibrosis><disease phenotype><driving><drug/agent><effective therapy><effective treatment><epigenetically><fibrosing interstitial lung disease><fibrosis in the lung><fibrotic interstitial lung disease><fibrotic lung disease><fibrotic pulmonary disease><follower of religion Jewish><histories><idiopathic pulmonary fibrosis><in vivo><inhibit IL-6><inhibit IL6><inhibit Interleukin-6><insight><instructor><interferon beta 2><lung fibrosis><lung injury><mAbs><medical college><medical schools><meeting><meetings><monoclonal Abs><mortality><mouse model><murine model><necrocytosis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><profibrotic fibroblast><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><repair><repaired><resistant><resolutions><response><school of medicine><skills><social role><summit><symposia><symposium><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tissue wound><transcription factor><translational clinician><translational physician><wound><wound healing><wound recovery><wound resolution><wounding><wounds>