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Interagency Autism Coordinating Committee (IACC)
Autism Research Database
Office of Autism Research Coordination (OARC)
 
Project Element Element Description

Project Title

Project Title

Macrophage Polarization and Utility of in Vivo Therapy with a Brain-Permeable Anti-TNF Agent in Models of Autism

Principal Investigator

Principal Investigator

Pearce, Bradley

Description

Description

Fiscal Year 2015 (FY15) Autism Research Program (ARP) Area(s) of Interest Addressed in the Proposed Research: Our application addresses two of the FY15 ARP Areas of Interest: (1) The role of environmental risk factors in autism spectrum disorder (ASD) pathophysiology and (2) assessment of novel therapeutics using valid preclinical models of ASD. Innovative Aspect of the Proposed Research: The proposed research is conceptually innovative because it addresses a novel hypothesis that shifts the paradigm in the field of ASD research away from a sole focus on deficits in fetal neurodevelopment and towards examination of alterations in fetal-maternal neuro-immune interactions as a result of maternal infection during pregnancy. Our research will test whether infection as a fetal-maternal insult alters the developmental trajectory by triggering chronic inflammatory cascades. Our overall strategy will be to induce maternal immune activation (MIA) with the viral mimic poly I:C, and then perform follow-up studies of our most promising findings by replicating the MIA models using a live virus (influenza). Impact of the Proposed Research Project on the Field of ASD Research: There has been little experimental examination of mechanisms underlying fetal-maternal neuro-immune interplay dysregulation, and our gene expression studies, manipulation of MIF and TNF, and neuroanatomical studies represent a congruent short-term approach to defining pathogenic mechanisms. In the long term, successful completion of this proposal will open the door for treatment during the postnatal period for fetuses at risk for ASD due to maternal infection if we are able to move the novel brain-permeant soluble TNF-selective biotherapeutic (XPro1595) to a clinical trial to interrupt the inflammatory cascade that results from MIA. Relevance to Autism Now: Prenatal infections or abnormal immune responses in children have been implicated in ASD, and immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of individuals with ASD. In the current study, we will focus on a pathway that integrates genetics, prenatal insults, and postnatal immune and neurodevelopmental disturbances in autism-like behaviors. Our translational focus to test the efficacy of a brain-permeant anti-inflammatory biologic (XPro1595) in robust preclinical models of MIA is very timely because XPro1595 is expected to begin clinical trials in ALS to treat the chronic neuroinflammation now believed to play a critical role in disease progression.

Funder

Funder

Department of Defense - Army

Fiscal Year Funding

Fiscal Year Funding

246807

Current Award Period

Current Award Period

2016-2018

Strategic Plan Question

Strategic Plan Question

Question 2: How Can I Understand What Is Happening?

Strategic Plan Objective

Strategic Plan Objective

Green dot: Objective has greater than or equal to the recommended funding. 2SA. Support at least four research projects to identify mechanisms of fever, metabolic and/or immune system interactions with the central nervous system that may influence ASD during prenatal-postnatal life by 2010. IACC Recommended Budget: $9,800,000 over 4 years. (Fever studies to be started by 2012.)

Project Link

Project Link

Macrophage Polarization and Utility of in Vivo Therapy with a Brain-Permeable Anti-TNF Agent in Models of Autism (External web link)

Institution

Institution

Emory University

State/Country

State/Country

Georgia

Project Number

Project Number

AR150035P1

Federal or Private?

Federal or Private?

Federal

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

Macrophage Polarization and Utility of in Vivo Therapy with a Brain-Permeable Anti-TNF Agent in Models of Autism | 282639 | 2015 | AR150035

 
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