# Systems biology of RNA Modifications in HIV/AIDS and Substance Use Disorders

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $442,914

## Abstract

Summary
 This is an “Alzheimer’s-Focused Administrative Supplement for NIH Grants that are Not Focused on
Alzheimer’s Disease” in response to NOT-AG-21-018. Emerging neuropathology findings in neuroHIV as well
as gene expression results from our group suggest a degree of pathogenic similarity and possibly overlap
between neuroHIV and Alzheimer’s Disease (AD). Additionally, the abuse of stimulants like cocaine and
methamphetamine (METH) is believed to increase the risk of dementias including AD, but experimental
evidence of the detrimental interaction of stimulants and AD are lacking.
 To address these knowledge gaps, we proposed to study the effects of stimulants in a rat transgenic (Tg)
model of AD, the McGill-R-Thy1-APP rat that expresses human APP751 with the Swedish and Indiana
mutations, under the control of the murine Thy1.2 promoter. The McGill-R-Thy1-APP rats have been
extensively characterized and show age-dependent accumulation of amyloid plaques, gliosis, cholinergic
synapse loss, and cognitive impairment. In particular, paralleling the studies of the parent grant, we aim to test
if histories of escalated self-administration of stimulants under conditions of extended daily access that results
in compulsive drug intake, will result in early onset of cognitive impairment in the McGill-R-Thy1-APP rats as
we have seen with 3xTg-AD Tg mice with a history of repeated alcohol intoxication. We will also use AD/HIV
double Tg rats to explore the possible interaction of AD and HIV mechanisms of pathogenesis. The proposed
studies will also determine if McGill-R-Thy1-APP rats differ from wild-type rats in motivation for stimulants and
propensity to escalate intake in the paradigm of extended access. The paradigm of escalated drug intake
under conditions of extended daily access is highly relevant to the human substance use disorder (SUD) as it
models all 7 of the criteria for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders
(DSM)-IV and 7 of the 11 criteria in the DSM-V. Paralleling the parent grant, we will conduct gene expression
analyses in a systems biology framework to dissect the gene regulatory networks involved in the interaction of
excessive stimulant intake with AD and with AD/HIV. This systems biology strategy identifies master regulatory
genes that drive the gene expression signatures associated to specific phenotypes and that will point to new
testable mechanistic hypotheses and candidate therapeutic targets for the progression of neurodegeneration in
AD, HIV, and stimulant abuse.
 The parent grant does not propose AD animal models, nor any AD-focused experiments and the PI has no
AD-related funds. The results of the present Administrative Supplement will lay the foundations for a new R01
proposal.

## Key facts

- **NIH application ID:** 10498540
- **Project number:** 3R01DA046170-05S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PIETRO P SANNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,914
- **Award type:** 3
- **Project period:** 2018-03-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498540

## Citation

> US National Institutes of Health, RePORTER application 10498540, Systems biology of RNA Modifications in HIV/AIDS and Substance Use Disorders (3R01DA046170-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10498540. Licensed CC0.

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