BUILDING A RESEARCH CAREER ON THE SERCA Becoming an Independent Veterinary Scientist

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BUILDING A RESEARCH CAREER ON THE SERCABecoming
an Independent Veterinary Scientist

• Ian Davis, DVM, PhD
• Assistant Professor
• Veterinary Biosciences

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BIOGRAPHY

• Veterinary School
• University of Bristol, England
• Graduate School
• University of Alabama at Birmingham
• Dept. of Comparative Medicine
• Mentor Patricia N. Fultz, Ph.D.
• Ph.D. thesis The role of apoptosis in the
  pathogenesis of primate lentivirus infections
• Residency in Laboratory Animal Medicine

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BIOGRAPHY 2

• Postdoctoral Experience
• University of Alabama at Birmingham
• Dept. of Anesthesiology
• Mentor Sadis Matalon, Ph.D.
• Research focus Effect of viral infections on
  respiratory epithelial cell function, using
  murine models
• Respiratory syncytial virus
• Sin Nombre virus

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ION TRANSPORT BY RESPIRATORY EPITHELIA
AIRSPACE LINING FLUID
INTERSTITIAL SPACE
ENaC
NaK ATPase
Na
3Na
2K
CFTR
?
Cl-
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AFC IS IMPAIRED IN ACUTE LUNG INJURY/ARDS
14/h
Ware Matthay, 2001
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IMPAIRED AFC IS ASSOCIATED WITH INCREASED ICU
MORTALITY
14/h
Ware Matthay, 2001
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WORDS TO LIVE BY
A dry lung is a happy lung Roy G. Brower
M.D. Johns Hopkins University
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SERCA HYPOTHESIS

• Respiratory syncytial virus infection of
  bronchoalveolar epithelial cells reduces their
  capacity to absorb Na ions
• Inhibition of Na transport will result in
  reduced alveolar fluid clearance (AFC)
• Reduced AFC may contribute to alveolar edema and
  hypoxemia in RSV bronchiolitis

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ALVEOLAR FLUID CLEARANCE
VENTILATE 160 bpm 100 O2
ECG
30 minutes
Protein concentrates as fluid leaves
ANESTHETIZE MOUSE
INSTILL 0.3 ml 5 BSA IN NaCl
ASPIRATE INSTILLED FLUID
37º C
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EFFECT OF RSV INFECTION ON ALVEOLAR FLUID
CLEARANCE


M
2
4
6
8
1
U
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EFFECT OF XAMR-0721 ON AFC AT DAY 2 P.I.

-

XAMR-0721
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BAL NUCLEOTIDE LEVELS AFTER RSV INFECTION


UTP
ATP
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SIGNIFICANT FINDINGS FROM SERCA

• RSV inhibits AFC by stimulating de novo
  pyrimidine synthesis and release of nucleotides
  into the alveolar lining fluid
• Released nucleotides act on P2Y purinergic
  receptors to reduce ENaC activity
• Inhibition of de novo pyrimidine synthesis is a
  promising therapeutic target for RSV
• Post-infection therapy reverses hypoxemia in
  RSV-infected mice
• RSV induces heterologous desensitization of
  bronchoalveolar epithelial b-adrenergic receptors
• May account for the lack of efficacy of
  b-agonists in children with RSV

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MAKING THE TRANSITION TO INDEPENDENCE

• Transfer to a new institution
• Recruited to Ohio State beginning June 2006
• End of Year 3 of SERCA
• Develop new lines of research
• Distinguish myself from my mentor
• Secure funding
• Keep the wolf from the door
• Develop internal and external collaborations
• Increase productivity

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NEW LINES OF RESEARCH

• Effects of RSV infection on airway function and
  responses to b-agonists in primary RSV infection
  and asthma models
• Role of dsRNA and other TLR ligands in inducing
  de novo nucleotide synthesis and release
• Effects of influenza virus infection on alveolar
  fluid clearance and airway function
• Role of nucleotides in pathogenesis of viral
  pneumonitis
• Viral infections in cystic fibrosis models
• Effects of ventilation pressure on alveolar fluid
  clearance

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FUNDING

• 10 funding applications submitted as P.I. since
  1/07
• 3 successful!
• American Heart Association BGIA
• Mechanisms of airway insensitivity to b-agonists
  after RSV infection
• OSU Public Health Preparedness in Infectious
  Diseases TIE Program
• Nucleotide synthesis inhibitors as novel
  therapies for hypoxemia induced by influenza
  virus infection
• NIAID Great Lakes Regional Center for Biodefense
  Individual Career Development Support Program for
  Faculty
• Nucleotide synthesis inhibitor therapy for
  hypoxemia in influenza infection

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INTERNAL COLLABORATIONS

• Amal Amer, PhD
• Influenza A virus pathogenesis in DF508 CFTR mice
• Kenneth Chan, PhD
• Effects of influenza A virus on the nucleotide
  profile of ATII cells
• Estelle Cormet-Boyaka, PhD
• Effects of influenza A virus on CFTR expression
  and function
• Joan Durbin, MD, PhD
• Influenza A virus pathogenesis in mice
• Daren Knoell, PharmD
• PTEN inhibitors in mice with oleic acid-induced
  ALI

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INTERNAL COLLABORATIONS

• Jeanette Marketon, PhD
• Mechanisms of glucocorticoid insensitivity in RSV
  infection
• Clay Marsh, MD
• Pulmonary function in murine models of COPD
• Virginia Sanders, PhD
• Pulmonary function in OVA-sensitized
  b2-adrenergic receptor-/- mice
• Mark Wewers, MD
• Role of ATP in inflammasome activation after
  influenza infection
• Karen Wood, MD
• RSV in allogeneic bone marrow transplant mice

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EXTERNAL COLLABORATIONS

• Eduardo Lazarowski, PhD, UNC
• Nucleotide analyses
• Rudolf Lucas, PhD, Medical College of Georgia
• Therapeutic efficacy of TNF-a tip peptide in
  viral pneumonitis
• Marty Moore, PhD, Emory University
• Pulmonary function in mice infected with clinical
  isolated of RSV
• Thomas Navratil, PhD, Inspire Pharmaceuticals
• Rho kinase inhibitors as RSV therapeutics
• Callum Semple, MD, University of Liverpool
• BAL nucleotide levels in children with RSV
  bronchiolitis
• Wayne Sullender, MD, UAB
• RSV b-agonist studies

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EFFECT OF INFLUENZA INFECTION ON ARTERIAL O2
SATURATION
n 10-20 per timepoint
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PROBLEMS WITH THE PROCESS

• Achieving independence from the mentor
• Are the ideas yours or his/hers?
• Will you end up in competition?
• Will your R01 be perceived as based on your work
  or theirs?
• Absence of an NCRR R01 Program
• Dealing with new program officers
• Other study sections seem less clear about what a
  SERCA is and how it prepares you for independence
• K01 designation seen as less prestigious than K08

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ACKNOWLEDGEMENTS

• Dr. Michael Lairmore
• Chair, Dept. of Veterinary Biosciences
• Zach Traylor
• My technician
• Current Funding Sources
• AHA
• OSU
• NIAID GLRCE
• NCRR
• Jack Harding