Abstract

Intracerebral hemorrhage (ICH) is a devastating type of stroke affecting more than 70,000 patients in the U.S. each year, yet there is no specific treatment available. Stimulation of the innate immune system at the site of hemorrhage leads to inflammation and progressive brain injury. In a murine model of ICH, we have demonstrated that ICH leads to the recruitment of blood-derived monocytes and inflammatory monocytes to the perihematomal region and the activation and proliferation of microglia. These events are concomitant with progressive functional disability. The proposed studies will utilize transgenic mice, bone marrow chimeras, and in vitro assays to determine the individual effects of each population on the immune response and functional outcomes after ICH.
Specific Aim 1 will determine the roles of the CX3CR1+ and CCR2+Gr1+ monocyte populations in injury after ICH.
In Specific Aim 2, the role of chemokine receptors CX3CR1 and CCR2 on microglial activation will be investigated. Together these studies will determine the translational potential of targetin these cellular responses in the treatment of ICH. This proposal outlines the training of Lauren Sansing, MD, an Assistant Professor in Neurology at the University of Connecticut Health Center, from mentored to independent translational researcher. Career development plans include formal coursework in immunology, regular seminar attendance in both immunology and neuroscience, and conference participation. These didactic components will complement the training involved in executing the research project and optimally position Dr. Sansing for a career as an independent investigator in translational stroke research.

Public Health Relevance

Intracerebral hemorrhage is a type of stroke that affects 70,000 people in the U.S. each year and causes half of the patients to die or be left severely disabled. This proposal will study the immune pathways responsible for brain injury surrounding the hemorrhage and hopes to identify new targets for treatment.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS078110-06
Application #
9123670
Study Section
NST-2 Subcommittee (NST)
Program Officer
Koenig, James I
Project Start
2014-09-03
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code

  Publications

Chang, Che-Feng; Goods, Brittany A; Askenase, Michael H et al. (2018) Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest 128:607-624
Taylor, Roslyn A; Chang, Che-Feng; Goods, Brittany A et al. (2017) TGF-?1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J Clin Invest 127:280-292
Manwani, Bharti; Stretz, Christoph; Sansing, Lauren H (2016) Stroke as the Initial Manifestation of the Human Immunodeficiency Virus. Stroke 47:e60-2
Askenase, Michael H; Sansing, Lauren H (2016) Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage. Semin Neurol 36:288-97
Sreekrishnan, Anirudh; Dearborn, Jennifer L; Greer, David M et al. (2016) Intracerebral Hemorrhage Location and Functional Outcomes of Patients: A Systematic Literature Review and Meta-Analysis. Neurocrit Care 25:384-391
Phelan, Christopher; Alaigh, Vivek; Fortunato, Gil et al. (2015) Effect of ?-Adrenergic Antagonists on In-Hospital Mortality after Ischemic Stroke. J Stroke Cerebrovasc Dis 24:1998-2004
Hammond, Matthew D; Taylor, Roslyn A; Mullen, Michael T et al. (2014) CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci 34:3901-9
Taylor, Roslyn A; Hammond, Matthew D; Ai, Youxi et al. (2014) CX3CR1 signaling on monocytes is dispensable after intracerebral hemorrhage. PLoS One 9:e114472
Hammond, Matthew D; Ambler, William G; Ai, Youxi et al. (2014) ?4 integrin is a regulator of leukocyte recruitment after experimental intracerebral hemorrhage. Stroke 45:2485-7
Shoup, J P; Winkler, J; Czap, A et al. (2014) ?-Blockers associated with no class-specific survival benefit in acute intracerebral hemorrhage. J Neurol Sci 336:127-31

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