Sex specific brain derived extracellular vesicle markers associated with chronic methamphetamine use

Sex specific brain derived extracellular vesicle markers associated with chronic methamphetamine use

Led by Dr. Sowmya YelamanchiliUniversity of Nebraska Medical Center

Study Overview:

Though often perceived to be a problem of the inner city, substance abuse has long been prevalent in rural areas. Rural adults have higher rates of alcohol abuse, tobacco use, and methamphetamine use, while prescription drug abuse and heroin use has grown in towns of every size. Factors contributing to substance abuse in rural America include- low education attainment, poverty, unemployment, high risk behaviors and isolation. The current proposal focuses on the potent psychostimulant methamphetamine (MA) that continues to pose a significant threat globally but importantly here in rural Nebraska.

Specific Aims:

(Aim 1): Identification of BDEV protein cargo signatures as potential sex specific markers for MA relapse using quantitative mass spectrometry-based proteomics.

(Aim 2): Detection of validated BDEV protein signatures in blood plasma from preclinical and clinical samples using an immunoaffinity approach

Study Sample Population:

In addition to our preclinical rat samples (which have already been collected), we will also isolate EVs from archived blood plasma from human subjects with a chronic history of meth dependency which are available from the Biobank at UNMC. The biobank employs rigorous criteria per the International Classification of Diseases, Tenth Revision, ICD-10) in identifying and classifying such samples. We currently have the availability of 17 plasma samples: 9 males, 8 females cataloged according to their race (12 caucasian, 2 black, 1 hispanic and 2 unknown race) and age (<30years =3; 30-40 years =8 and 40-60 years= 6) with a history of meth use. These samples were selected per the ICD10 criteria F15.1 and F15.2 that includes amphetamine related disorders and excludes cocaine related disorders. [Note: Since these are archived samples, they are exempt from human subjects’ studies]. Control subjects are balanced for both genders, race, age and carefully screened to exclude for any cancers and/or severe liver and kidney diseases.

Unique Study Procedures:

1. BDEV isolation and characterization

2. Plasma EV isolation and characterization

3. Immunocapturing validated BDE markers in blood plasma

Long-Term Goals:

Rural communities make up 97% of America’s land area, yet less than 20% of the population lives in these smaller communities. Many don’t suspect these seemingly idyllic rural areas are impacted by substance abuse — a disease that wreaks havoc on both individuals and their families. From the early 2000s, the number of substance use-related deaths in rural communities has risen, especially in comparison to deaths in urban areas. The proposed research aims to address a very important question on decoding sex differences associated with MA abuse given the widespread use of MA in rural Nebraska. On completion of these studies, we anticipate filling a significant gap in knowledge on how impaired BDEV dynamics affects neuronal function between the sexes during meth reinstatement including identification of key BDEV proteins as potential biomarkers. The wealth of information arising will break new ground and importantly provide novel proof of concept studies which will further as a prelude to future basic research on developing EVs as sex-specific medication development for treating meth addiction. Importantly, the proposed research encompassing preclinical and clinical samples fit aptly to the mission of RDAR – “advancing understanding of causes, impacts, and interventions related to rural drug addiction using both preclinical studies to field-based behavioral, neural, social, clinical, and translational research”.

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Sowmya Yelamanchili

Dr. Sowmya YelamanchiliPROJECT Director

The long term goals of my independent research program are to understand the role of regulatory molecules such as genes, proteins and microRNAs in the pathogenesis of neurological disorders and in the field of drug addiction, specifically methamphetamine abuse. Over the last six years, my lab has been extensively studying the role of extracellular vesicles (EVs) which express a repertoire of cargo (cf. proteins, miRNA, lipids etc.) in an array of neurodegenerative and neurodevelopmental disorders. My lab uses various model systems including human biospecimens, rhesus macaques in addition to rodent models and in vitro based approaches to study brain dysfunction associated with chronic drug use. On these lines, my own research program focuses on investigating the role of extracellular vesicles in chronic methamphetamine (meth) abuse as well as sex differences associated with meth relapse. My lab has also shown significant success in standardizing EV isolation and characterizing the role of brain derived EVs (BDEs) in an array of neurological disorders cf. NeuroAIDS, Traumatic Brain Injury and in Methamphetamine/ Prescription opioid/Nicotine use disorders.

Full Sowmya Yelamanchili bio