R35NS132184
Project Grant
Overview
Grant Description
Role of RNAs in Post-Stroke Brain Damage - Cerebral ischemia significantly alters the expression and/or function of transcriptional and translational mechanisms including various classes of noncoding RNAs, epigenetics, and epitrancriptomics.
My research in the past 20 years evaluated these mechanisms that are central in promoting either secondary brain damage or recovery after stroke with a goal to design novel therapies.
In the 7 years, I will focus on studying the role of various RNAs in promoting post-stroke brain damage. The goal is to understand the mechanisms as well as identifying new therapeutic targets to minimize the secondary brain damage and to promote functional recovery after stroke.
In this R35, I propose 4 projects.
Project 1: In a currently funded RO1 grant we are evaluating the functional significance of an epigenetic modification called DNA hydroxymethylation (5HMC). Our studies so far showed that stroke leads to induction of 5HMC in many prosurvival genes that induces their expression. We intriguingly observed that many lncRNA induced after stroke also show increased 5HMC levels. In this project, we will continue the studies to understand the significance of 5HMC induction in lncRNAs to post-stroke functional outcomes.
Project 2: RNAs can be tagged by >150 distinct chemical modifications, which are collectively defined as epitrancriptomic modifications that form an additional layer of post-transcriptional gene regulation. Among them, methylation of the adenosine at N6-position (N6-methyladenosine; m6A) is the most abundant modification in the brain. Our studies show that focal ischemia downregulates m6A demethylase FTO leading to increased abundance of m6A-tagged mRNAs. Many of these are inflammatory and apoptotic. Furthermore, activation of FTO promotes RNA demethylation and neuroprotection. We will use molecular tools to evaluate the functional significance and mechanisms of increased m6A methylation of RNAs in brain damage after stroke.
Project 3: RNAs can also undergo the epitrancriptomics modification of glycation and the neural glycornas interact with microglial SIGLEC receptors to dampen inflammation following CNS insults. We will study the significance of glycornas and the mechanism of action in brain after stroke.
Project 4: Various classes of RNAs collaborate in their actions. We particularly observed that circular RNAs interact with lncRNAs to modulate mRNAs and microRNAs. We will analyze the role of RNA networks in relation to ischemic brain damage using 2 examples.
Project 4A: The first one is the interaction of a circRNA (circPUM1) with a lncRNA (NORAD) to control a mRNA that codes an RNA binding protein (PUM1) and a mRNA that codes BNIP2.
Project 4B: An ongoing RO1 is studying the role of miR-7 in controlling α-synuclein in post-stroke brain. Although mature miR-7 levels decrease after stroke, levels of pre-miR-7a and 7b are not altered. As circRNA CDR1as binds and stabilizes miR-7, we are planning to study the interactive role of this CDR1as-miR-7-α-synuclein in mediating post-ischemic brain damage.
Overall, the above projects are all focused to evaluate the significance of various RNAs with a goal to find new mechanisms and new targets to design future molecular therapies to curtail post-stroke brain damage.
My research in the past 20 years evaluated these mechanisms that are central in promoting either secondary brain damage or recovery after stroke with a goal to design novel therapies.
In the 7 years, I will focus on studying the role of various RNAs in promoting post-stroke brain damage. The goal is to understand the mechanisms as well as identifying new therapeutic targets to minimize the secondary brain damage and to promote functional recovery after stroke.
In this R35, I propose 4 projects.
Project 1: In a currently funded RO1 grant we are evaluating the functional significance of an epigenetic modification called DNA hydroxymethylation (5HMC). Our studies so far showed that stroke leads to induction of 5HMC in many prosurvival genes that induces their expression. We intriguingly observed that many lncRNA induced after stroke also show increased 5HMC levels. In this project, we will continue the studies to understand the significance of 5HMC induction in lncRNAs to post-stroke functional outcomes.
Project 2: RNAs can be tagged by >150 distinct chemical modifications, which are collectively defined as epitrancriptomic modifications that form an additional layer of post-transcriptional gene regulation. Among them, methylation of the adenosine at N6-position (N6-methyladenosine; m6A) is the most abundant modification in the brain. Our studies show that focal ischemia downregulates m6A demethylase FTO leading to increased abundance of m6A-tagged mRNAs. Many of these are inflammatory and apoptotic. Furthermore, activation of FTO promotes RNA demethylation and neuroprotection. We will use molecular tools to evaluate the functional significance and mechanisms of increased m6A methylation of RNAs in brain damage after stroke.
Project 3: RNAs can also undergo the epitrancriptomics modification of glycation and the neural glycornas interact with microglial SIGLEC receptors to dampen inflammation following CNS insults. We will study the significance of glycornas and the mechanism of action in brain after stroke.
Project 4: Various classes of RNAs collaborate in their actions. We particularly observed that circular RNAs interact with lncRNAs to modulate mRNAs and microRNAs. We will analyze the role of RNA networks in relation to ischemic brain damage using 2 examples.
Project 4A: The first one is the interaction of a circRNA (circPUM1) with a lncRNA (NORAD) to control a mRNA that codes an RNA binding protein (PUM1) and a mRNA that codes BNIP2.
Project 4B: An ongoing RO1 is studying the role of miR-7 in controlling α-synuclein in post-stroke brain. Although mature miR-7 levels decrease after stroke, levels of pre-miR-7a and 7b are not altered. As circRNA CDR1as binds and stabilizes miR-7, we are planning to study the interactive role of this CDR1as-miR-7-α-synuclein in mediating post-ischemic brain damage.
Overall, the above projects are all focused to evaluate the significance of various RNAs with a goal to find new mechanisms and new targets to design future molecular therapies to curtail post-stroke brain damage.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Madison,
Wisconsin
53715
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 563% from $615,716 to $4,079,378.
University Of Wisconsin System was awarded
RNA Mechanisms in Post-Stroke Brain Damage: Novel Therapeutic Targets
Project Grant R35NS132184
worth $4,079,378
from the National Institute of Neurological Disorders and Stroke in May 2023 with work to be completed primarily in Madison Wisconsin United States.
The grant
has a duration of 8 years and
was awarded through assistance program 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders.
The Project Grant was awarded through grant opportunity Research Program Award (R35 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 5/21/26
Period of Performance
5/1/23
Start Date
4/30/31
End Date
Funding Split
$4.1M
Federal Obligation
$0.0
Non-Federal Obligation
$4.1M
Total Obligated
Activity Timeline
Transaction History
Modifications to R35NS132184
Additional Detail
Award ID FAIN
R35NS132184
SAI Number
R35NS132184-197817873
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Funding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Awardee UEI
LCLSJAGTNZQ7
Awardee CAGE
09FZ2
Performance District
WI-02
Senators
Tammy Baldwin
Ron Johnson
Ron Johnson
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of Neurological Disorders and Stroke, National Institutes of Health, Health and Human Services (075-0886) | Health research and training | Grants, subsidies, and contributions (41.0) | $615,716 | 100% |
Modified: 5/21/26