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Mechanisms of Innate and Acquired Host Defense and Tissue Injury in Skin

Award Number: R01AR059126
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2010
PERIOD OF PERFORMANCE END DATE: 05/31/2015

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Mechanisms of Innate and Acquired Host Defense and Tissue Injury in Skin - DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to gain insight into the mechanisms of immunity, inflammation and tissue injury in the host response to cutaneous infection. Leprosy provides a model for studying the interaction between the systemic and local immune responses in skin, because its diverse clinical manifestations correlate with the host immune response to the pathogen, Mycobacterium leprae. In the tuberculoid (T-lep) form of disease, the infection is self-healing, with few bacteria in few skin lesions, while in the lepromatous (L-lep) form, the infection is progressive, with high bacterial loads in disseminated skin lesions. Furthermore, patients develop immunologic reactions, permitting the study of acute inflammation over time. We have elected to focus on the Th17 and recently identified Th22 cells and their role in leprosy, given our exciting preliminary data linking Th17 cells at the site of disease in the self-limited form of leprosy, tuberculoid (T-lep) and Th22 cells to the acute inflammatory reactional state, erythema nodosum leprosum (ENL). These findings form the basis for our central hypothesis that Th17 cells contribute to host defense in response to microbial infection in skin, whereas in contrast, Th22 cells contribute to acute inflammation and immune-mediated tissue injury. The revised specific aims are to investigate: 1) the mechanisms by which the innate immune system recognizes M. leprae and triggers the induction of Th17 vs. Th22 cells, 2) the mechanisms by which Th17 and Th22 cells contribute to host defense, and, 3) the mechanisms inducing Th17 and Th22 to trigger neutrophil recruitment, a key factor in acute inflammation and immune-mediated tissue injury. By studying the differential role of Th17 and Th22 cells in skin lesions from across the spectrum of leprosy as model, we hope to target an integrated understanding by which the innate immune response influences the adaptive response with relevance to host defense and tissue injury in the context of microbial infection in humans, and, we would hope, would provide the ability to predict disease outcome and also lead to the development of new immunomodulatory treatments for a variety of infectious and skin diseases. PUBLIC HEALTH RELEVANCE: Leprosy continues as a major health and economic burden in developing countries and also provides an extraordinary model to study human immune responses to a microbial pathogen because it is a skin disease, such that the lesions are readily accessible for study of immune processes at the site of disease. Our preliminary data demonstrate unique insights into human immune responses from the study of leprosy, including the biologic/immunologic pathways that contribute to resistance vs. susceptibility to progressive infection. The investigation of these aspects of host defense mechanisms will yield new insights into the human immune system as well as provide novel targets for therapeutic intervention against a variety of infectious and skin diseases.


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: 2014 ( Subtotal = $390,126 )
2014	2014	JOHN WAYNE CANCER INSTITUTE	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/2/2014	NON-COMPETING CONTINUATION	$390,126
														Subtotal = $390,126

Issue Date FY: 2013 ( Subtotal = $378,184 )
2013	2013	JOHN WAYNE INSTITUTE FOR CANCER TREATMENT & RSCH	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/31/2013	NON-COMPETING CONTINUATION	$378,184
														Subtotal = $378,184

Issue Date FY: 2012 ( Subtotal = $398,088 )
2012	2012	JOHN WAYNE INSTITUTE FOR CANCER TREATMENT & RSCH	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/28/2012	NON-COMPETING CONTINUATION	$398,088
														Subtotal = $398,088

Issue Date FY: 2011 ( Subtotal = $398,088 )
2011	2011	JOHN WAYNE INSTITUTE FOR CANCER TREATMENT & RSCH	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	6/4/2011	NON-COMPETING CONTINUATION	$398,088
2011	2010	JOHN WAYNE INSTITUTE FOR CANCER TREATMENT & RSCH	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/16/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$192,184
2011	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	5/16/2011	NEW	-$192,184
														Subtotal = $398,088

Issue Date FY: 2010 ( Subtotal = $346,500 )
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/28/2010	NEW	$346,500
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	7/19/2010	NEW	$0
														Subtotal = $346,500

Grand Total All Awards = $1,910,986

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Mechanisms of Innate and Acquired Host Defense and Tissue Injury in Skin

Award Number: R01AR059126

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2010

PERIOD OF PERFORMANCE END DATE: 05/31/2015

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