Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Allosteric regulation and phosphorylation homeostasis of PEA-15 in protection of brain microvascular endothelial cells against methamphetamine and HIV-1 Tat

Award Number: R21DA046223
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2022

Group Awards By:

View Award Description

Allosteric regulation and phosphorylation homeostasis of PEA-15 in protection of brain microvascular endothelial cells against methamphetamine and HIV-1 Tat - Project Summary Methamphetamine (METH) is the most commonly synthesized and heavily abused illicit drug in the United States and around the world. Significant populations of METH abusers are also infected with the human immunodeficiency virus (HIV)-1 or of high risk of developing HIV-1 infection. As a highly addictive phychostimulant, METH can cause cognitive damage by exerting its actions on neurons, and enhance the damage of HIV on the CNS by compromising the integrity of the blood-brain barrier (BBB). The BBB consists of brain microvascular endothelial cells (BMVECs), astrocytes, and pericytes. BMVECs are specialized endothelial cells that line the capillaries within the brain and control the flow of substances between the blood circulation and the brain parenchyma. METH is well known to exert detrimental effects on the BMVECs, and to compromise the BBB. HIV-1 infection can accelerate endothelial cell death through elevated tumor necrosis factor (TNF)-α-induced apoptotic pathway. Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15) plays a neural protective role by inhibiting TNFα-induced cell death, and its functions are tightly regulated by the phosphorylation states on the irregularly structured C-terminal tail. It has been reported that substance abuse, including METH, can greatly alter the phosphorylation states of PEA-15 while the overall PEA-15 expression level is relatively constant. Recently, we first proposed a phosphorylation homeostasis model, in which various phosphorylation states of PEA-15 must be balanced in different cell types and tissues, and any disruption of this delicate balance could be harmful to the cells and tissues. Despite the importance of this phosphorylation homeostasis in the neuroprotection, little is known regarding the underlying mechanism and regulation of PEA-15 in preventing apoptosis and how METH and HIV-1 can affect PEA-15's protective effect by altering its phosphorylation homeostasis. Particularly the structures and regulations of PEA-15 in the formation of death-inducing signaling complex (DISC) initiated by TNFα are yet to be elucidated. Based on the recent literature and our preliminary studies, we hypothesize that the conformation of PEA-15 DED, and consequently its binding specificity, is allosterically modulated by the status of the C-terminal tail, and METH and HIV-1 target the allostery of PEA-15 to promote apoptosis at the endothelium. To test our hypothesis, we propose the following two specific aims: (1) To elucidate the mechanistic connection between METH and HIV-induced endothelial cell death and phosphorylation homeostasis of PEA-15.; and (2) To delineate the relevant conformations and allosteric control of PEA-15 within cellular contents and the mechanism of PEA-15 in alleviation of the detrimental effects of METH and HIV-1 Tat on primary BMVECs using novel in-cell NMR techniques. In this Cutting-Edge Basic Research Awards (CEBRA) application, we will substantiate the novel concept of phosphorylation homeostasis of PEA-15 and its important prohibition of apoptosis and crucial protection of the BBB in the context of METH abuse and HIV infection. We will examine the allosteric control of DISC formation and caspase-8 activation by phosphorylation of PEA- 15 using novel in-cell NMR techniques. This study is innovative because, to our knowledge, this will be the first study of potential antiapoptotic effects of PEA-15 in the context of METH/HIV-1 induced endothelial cell death and BBB disruption. In addition, there is no structural information is currently available for DISC with and without PEA-15 at atomic level, and it is unclear how cellular environment and extracellular stimuli could affect the intersection of death and survival, which PEA-15 plays a critical role in the regulation. Our study is highly significant and clinically relevant because it will provide valuable information on the mechanisms underlying the detrimental effects on BBB of METH abuse in the context of HIV-1 infection, which can help to develop therapeutic strategies to protect the BBB integrity from METH-induced dysregulation of immune responses with HIV-1 infection.


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: 2024 ( Subtotal = $0 )
2024	2019	NEW JERSEY CITY UNIVERSITY	2039 JOHN F KENNEDY BLVD	JERSEY CITY	NJ	07305	HUDSON	USA	Drug Use and Addiction Research Programs	000	2	10/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	NEW JERSEY CITY UNIVERSITY	2039 JOHN F KENNEDY BLVD STE 105	JERSEY CITY	NJ	07305	HUDSON	USA	Drug Use and Addiction Research Programs	000	2	9/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $143,355 )
2019	2019	NEW JERSEY CITY UNIVERSITY	2039 JOHN F KENNEDY BLVD STE 105	JERSEY CITY	NJ	07305	HUDSON	USA	Drug Use and Addiction Research Programs	000	2	8/12/2019	NON-COMPETING CONTINUATION	$143,355
														Subtotal = $143,355

Issue Date FY: 2018 ( Subtotal = $143,355 )
2018	2018	NEW JERSEY CITY UNIVERSITY	2039 JOHN F KENNEDY BLVD STE 105	JERSEY CITY	NJ	07305	HUDSON	USA	Drug Use and Addiction Research Programs	000	1	9/14/2018	NEW	$143,355
														Subtotal = $143,355

Grand Total All Awards = $286,710

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Allosteric regulation and phosphorylation homeostasis of PEA-15 in protection of brain microvascular endothelial cells against methamphetamine and HIV-1 Tat

Award Number: R21DA046223

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer