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AIRWAY HYPER-RESPONSIVENESS: FROM MOLECULE TO ORGAN

Award Number: R33HL087792
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2011

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AIRWAY HYPER-RESPONSIVENESS: FROM MOLECULE TO ORGAN - DESCRIPTION (provided by applicant): Summary: Asthmatic lungs typically respond to inhaled allergens with exaggerated reductions in airway function. This phenomenon is termed airway hyper-responsiveness (AHR) and can be life threatening. AHR is not a simple reaction but is the culmination of multiple processes that manifest over a huge range of length and time scales. At one extreme, molecular signaling and interactions determine the force generated by airway smooth muscle cells (ASMCs). At the other extreme, contraction of the ASMCs is converted into a dynamic and complex constriction of branched airways that patients perceive by increased difficulty in breathing. Furthermore, asthma therapies are predominately pharmacological and operate at the molecular level, yet clinical outcomes are measured at the level of the whole lung. These two extremes are linked by numerous events operating at intermediate ranges of scale. These complex characteristics of AHR limit our understanding and ability to control asthma and will continue to confound research studies that only address responses at a single scale. Complex multi-scale systems cannot, by their very nature, be understood by studies limited to a few parameters. Consequently, this proposal will follow the innovative and alternative systems approach of developing a multi-scale experimental and computational model of AHR. We will initially determine how Ca2+ oscillations and the kinetics of cross-bridge cycling between actin and myosin molecules determine force production by ASMCs. Subsequently, we will determine how this force production distorts the airway wall and brings about airway narrowing throughout the lung. This will be achieved by the collaboration of a multidisciplinary group of investigators with experimental and mathematical expertise who will integrate our current knowledge and understanding of AHR at different cellular and tissue levels into a mathematical and computational model of AHR. The model will initially include phenomena that meet the criteria of being essential for airway contraction, of clear importance to AHR and experimentally accessible for iterative validation. In future studies, this model will be refined by the addition of relevant details. The model will be used to make specific predictions of molecular, cellular and tissue behavior and suggest critical experiments. In combination with extensive iteration between theory and experimentation, the sub-sections of the model will be refined and validated to identify the fundamental parameters that link the successive processes or scales. The results of this investigation will lead to an improved understanding of the link between the basic cellular pathophysiology and the whole lung response in asthma and other obstructive lung diseases This will improve the diagnosis of cause and effectiveness of treatment of these diseases. In addition, because AHR is clearly a complicated symptom, this investigation will evaluate the effectiveness of addressing disease with a systems biology approach. Many individuals in the USA suffer from asthma, a condition that is characterized by an exaggerated airway contraction or airway hyper-responsiveness (AHR). This response is extremely complicated being initiated at the molecular level by airborne allergens or stimuli and culminating at the organ level with difficulty in breathing. The objective of this research is to develop an understanding of this sequence of events by using a mathematical framework to guide and integrate experimental studies that elucidate the details of each process involved. With this approach, the key events in AHR can be identified and targeted for therapeutic intervention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2010 ( Subtotal = $0 )
2010	2009	AUCKLAND UNISERVICES, LTD	20 SYMONDS STREET	AUCKLAND				NZL	Lung Diseases Research	000	3	7/19/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $98,159 )
2009	2009	AUCKLAND UNISERVICES LIMITED	70 SYMONDS ST PRIVATE BAG 92019	AUCKLAND				NZL	Lung Diseases Research	000	3	5/20/2009	NON-COMPETING CONTINUATION	$98,159
														Subtotal = $98,159

Issue Date FY: 2008 ( Subtotal = $106,083 )
2008	2008	AUCKLAND UNISERVICES, LTD	20 SYMONDS STREET	AUCKLAND				NZL	Lung Diseases Research	000	2	5/16/2008	NON-COMPETING CONTINUATION	$106,083
														Subtotal = $106,083

Issue Date FY: 2007 ( Subtotal = $103,506 )
2007	2007	AUCKLAND UNISERVICES, LTD	20 SYMONDS STREET	AUCKLAND				NZL	Lung Diseases Research	000	1	7/23/2007	NEW	$103,506
														Subtotal = $103,506

Grand Total All Awards = $307,748

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AIRWAY HYPER-RESPONSIVENESS: FROM MOLECULE TO ORGAN

Award Number: R33HL087792

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2011

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