R35NS132265

Sex Differences in Inflammation Across the Lifespan - Project Summary

Stroke affects over 15 million people worldwide each year and remains the leading cause of disability in the United States. The economic burden of stroke is increasing as the population ages, making the prevention and treatment of vascular disease a critical public health issue.

Elderly women are a third more likely to develop post-stroke depression, have greater rates of post-stroke cognitive decline, and have poorer quality of life after stroke compared to age-matched men. Many biological factors contribute to these disparities, including social factors, intrinsic sex differences in cell death, and chromosomal sex.

As neonates, male mice (and boys) are more sensitive to ischemia. However, with aging, female mice (and women) have worse outcomes, in part due to loss of estrogen with reproductive senescence. We have found that genes on the X chromosome that escape inactivation contribute to significant sex differences in the inflammatory response, both in the brain (microglia) and in the periphery. We have extended our work to examine sex differences in adipose tissue, in the gut (and its microbiome), and in the cerebral vasculature.

My research focuses on elucidating the fundamental mechanisms responsible for sex and age differences in cell death, inflammatory responses, and neural repair throughout the lifespan. The goal of my program is to translate these findings into novel, targeted therapies for use in patients of both sexes.

Over the past 20 years, our NINDS-funded research program has pioneered work that has improved our understanding of how sex contributes to cell death. We have a particular emphasis on cerebrovascular diseases and have developed programs investigating neonatal injury, vascular dementia, and stroke. Our studies have revealed that sex differences contribute to the response to brain injury and in the efficacy of a variety of neuroprotective agents.

The growing recognition that sex is a critical biological variable has led to changes in NIH policy, which now mandates inclusion of females in pre-clinical studies. Sex differences have also been identified in the clinical setting. Recognition of these factors has led to sex disaggregation of clinical trial outcomes and an improved understanding of factors that contribute to low enrollment of women in trials.

In this application, we will consolidate three ongoing NINDS-funded proposals that focus on 1.) age-related inflammation, 2.) the chromosomal contribution to stroke, and 3.) the detrimental effects of social isolation. We will leverage our existing knowledge to produce new research that challenges the existing paradigm by integrating information across these areas. Our research protocol will build on our past successes using cutting-edge neurophysiological, immunological, and behavioral tools.

Successful completion of this research will increase our understanding of sex in other neurological disorders. My long-term goal is to maximize outcomes for all patients affected by neurological disease.

University Of Texas Health Science Center At Houston

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Houston, Texas 77030 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-22-038)

Amendment Since initial award the total obligations have increased 220% from $1,048,212 to $3,353,112.