This administrative supplement application is submitted for the parent award (5R01AI124465- 05) in response to NIH funding opportunity (NOT-AG-20-008), entitled ?Alzheimer?s-focused administrative supplements for NIH grants that are not focused on Alzheimer?s disease.? Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder of aging, affecting about 44 million people worldwide with 5.5 million in the U.S. Amyloid plaques in the brain are one of the pathological hallmarks of AD. The plaques mainly consist of fibrillary forms of amyloid ? peptide-40 (A?-40) and amyloid ? peptide-42 (A?-42) produced from amyloid precursor proteins by sequential cleavage. Despite the major drug development efforts targeting amyloid ? peptide cleavage and processing, nearly all experimental drugs tested for AD thus far have failed to show significant efficacy. Recent studies show that A? peptides form aggregates that induce oxidative stress and initiate the inflammatory process, leading to activation of microglial and neurodegeneration in the brain, which is fueled by proinflammatory cytokines secreted by CD4+ T-helper 17 (Th17) cells. These studies suggest a new therapeutic strategy of targeting neuroinflammatory Th17 cells in the AD pathogenesis to prevent and treat AD. Studies from us and others show that Th17 cell differentiation from nave CD4+ T cells is tightly regulated in gene transcription by coordinated activities of major transcription and chromatin regulators including BET family protein BRD4. We recently developed a set of novel small-molecule compounds that selectively target BRD4 activity for transcriptional expression of Th17 signature cytokines including IL-17, IL-21, IL-22, and IL-23, and blocks over-development of Th17 cells in mice that mimic the conditions of neuroinflammatory disorders in humans. Motivated by our favorable findings, in this study, we propose to: (1) develop our CNS penetrant Th17 immunomodulators, and (2) characterize them in the AD mouse model as a new immunomodulation treatment for AD, which represents a major unmet medical need.

Public Health Relevance

Proinflammatory Th17 cells have been implicated in the progression of Alzheimer?s disease (AD). However, we have limited understanding of their role in neuroinflammation that drives the AD pathogenesis. In this study we explore the therapeutic potential of pharmacological inhibition of the production of proinflammatory Th17 cytokines as new immunomodulation therapy for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI124465-05S2
Application #
10121773
Study Section
Program Officer
Mallia, Conrad M
Project Start
2016-03-10
Project End
2021-02-28
Budget Start
2020-08-06
Budget End
2021-02-28
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Zaware, Nilesh; Zhou, Ming-Ming (2017) Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation. Curr Opin Chem Biol 39:116-125
Cheung, Kalung; Lu, Geming; Sharma, Rajal et al. (2017) BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. Proc Natl Acad Sci U S A 114:2952-2957
Cheung, Ka Lung; Zhang, Fan; Jaganathan, Anbalagan et al. (2017) Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation. Mol Cell 65:1068-1080.e5
Zhang, Qiang; Zeng, Lei; Zhao, Chengcheng et al. (2016) Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure 24:1606-12
Aguilo, Francesca; Li, SiDe; Balasubramaniyan, Natarajan et al. (2016) Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1?. Cell Rep 14:479-492
Meslamani, Jamel; Smith, Steven G; Sanchez, Roberto et al. (2016) Structural features and inhibitors of bromodomains. Drug Discov Today Technol 19:3-15
Zhang, Qiang; Zeng, Lei; Shen, Chen et al. (2016) Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4. Structure 24:1201-8