Chronic/Lifestyle Diseases

Overview

Chronic or the Non-communicable diseases are on the rise across the globe accounting for 73% of all deaths. In India, non-communicable diseases accounts for 53% of all deaths and 44 % of disability-adjusted life-years lost. India is home to more than a sixth of the world’s population and has been witnessing rapid epidemiological transition i.e, a shift from communicable to non-communicable diseases (NCDs) along with socio-economic development.

As per the recent study report on “India: Health of the Nation's States” by Ministry of Health & Family Welfare, it is estimated that the proportion of deaths due to Non-Communicable Diseases (NCDs) in India have increased from 37.9% in 1990 to 61.8% in 2016. The four major disease burden attributable to NCDs in India are cardiovascular diseases (CVDs), cancers, chronic respiratory diseases (CRDs) and diabetes. India suffers loss of life at an early age due to cardiovascular diseases which account for one fourth of all deaths having recorded a steep increase in hypertension both in rural and urban population. The National Health Policy of India, in accordance with Sustainable Development Goals, aims to reduce the premature mortality from non-communicable diseases (NCD) by one-third by 2030.

Mandate

The Department of Biotechnology under its ‘Chronic/Lifestyle Disease Program’ over the decades has taken strides to support and promote basic, clinical, translational and interdisciplinary research in focused high disease burden areas of the country such as Diabetes, Cardiovascular Diseases, Liver & Kidney Disorders, Respiratory/lung disease, Autoimmune Diseases, Skin, Bone & Muscular Diseases, Eye disorders etc to delineate the mechanistic insights of the underlying diseases and further underpinning the physiological and pathological aspects of the diseases towards developing potential therapeutic strategies through biotechnological interventions.

Thrust Areas

Besides supporting R&D activities focused on the biology and pathophysiology of the disease, the present thrust is to leverage advanced cutting edge technologies and innovations for combating chronic diseases through interdisciplinary approach in order to develop early screening tools, identify predictive biomarkers, develop risk stratification models for prevention, treatment and reversal of chronic diseases.

Salient Achievements

Few significant achievements emanated from the major programs / research projectsare as follows:

Indian Chronic Kidney Disease (ICKD) Study:

The ICKD Phase I study has established a countrywide prospective cohort of early stage Chronic Kidney Disease patients which had enrolled >4300 patients across 11 centers across India. The study has created a national resource to define and identify risk factors for progression of CKD in Indian population. Analysis of baseline subjects shows unique characteristics for Indian subjects which reinforce the need for and value of the data from this cohort. The study is aimed at understanding the clinical behaviour in terms of disease progression and disease complications during follow-up of chronic kidney patients enrolled in first phase of study. The study has shown several findings around the association of quality of life with socioeconomic rather than medical factors, unmet treatment needs in the study of prescription patterns, gaps in the overall quality of care. One unique finding is the first-time strong and independent association demonstration of serum free catalytic iron with composite major adverse kidney events in patients with CKD despite adjustment for gender, age, occupational exposure, hypertension, diabetes, tobacco, alcohol, history of acute kidney injury and eGFR. This finding has opened the door to a randomised clinical trial of iron chelation therapy. Another analysis shows that ACEI/ARB use is associated with slower rate of decline in eGFR in those with CKD stage 1-3. ACEI/ARB users had a significantly lower risk of renal outcomes, and cardiovascular mortality.

Multi-institutional Network Program on Systemic Lupus Erythematosus: Understanding the Diversity of SLE

First prospective inception cohort on Systemic lupus erythematosus for research (INSPIRE) has been developed from across India of 2503 patients. The study has revealed phenotypic heterogeneity across different parts of the country. Autoantibody profile suggests high prevalence of Lupus specific antibodies: anti-Sm and anti Ribo-P antibodies in Indian population. Antibody clusters suggest co-occurrence of autoantibodies associated with specific phenotypes.Gastrointestinal involvement is associated with higher disease activity and mortality.A low-cost calculator has been developed comprising of age, CRP and total leucocyte count that is able to differentiate between infection and flare. The calculator has been validatedand found to have good prediction. In a sub-study, it is found that about 2/3rd of patients with SLE have vitamin D deficiency/insufficiency which is much more in North India. High dose vitamin D (60,000 weekly X 5 dose and then monthly) improves vitamin D levels but has no impact on disease activity and nor does it prevent flares. Vitamin D levels do not show any association with disease activity or Type I IFN regulated proteins. The project has also established a biorepository as part of the study (blood and urine samples). This is a rare resource of longitudinal samples from patients with SLE which can be used for biomarker analysis. Further, DNA samples of 2028 patients are available for Genome studies.

Social Responsibility: The project has also helped to develop a patient support group for SLE which is helping each other as well as increasing awareness of SLE in community through social media. The project personnel provided moral as well as social support to these 2500 patients to tide over the COVID pandemic as well as helped them get financial assistance if needed.

Tailor-Made Peptidomimetics Designing against Human Islet Amyloid Polypeptide (hIAPP) Aggregation

Islet amyloid polypeptide (IAPP) is a 37 amino acid hormone that has long been associated with the progression of type II diabetes mellitus disease. Toxic deposition of human Islet Amyloid Polypeptide (hIAPP) on the pancreas is known to affect normal β-cell function. Specifically, hIAPP in conjunction with insulin control the plasma glucose levels, however, hIAPP aggregates in the pancreatic β-cells of T2DM form highly ordered and stable amyloid fibrils, similar as Parkinson, Alzheimer and Huntington diseases. Thus in this study, a novel beta-sheet breaker peptidomimetics (BSBHps) and cyclic cBSBHps were developed to inhibit hIAPP fibrillation and disruption of already formed fibril to non-toxic oligomers. The designed peptides were shown to protect the model beta cell membrane from its damage by hIAPP, suggesting that the designed peptides are effective to inhibit the hIAPP induced membrane disruption with more pronounced effect with cyclic peptides

Effect of Rifampicin and its analogs on Glucose-induced Life span shortening and AGE Modifications

Advanced Glycation Endproducts (AGEs) are formed when glucose reacts non‐enzymatically with proteins, leading to abnormal protein function, oxidative stress and inflammation. AGEs are associated with aging and age‐related diseases, and are highly aggravated in diabetes due to higher exposure of proteins to glucose. Therefore, drugs preventing AGE formation have the potential to treat diabetic complications, positively affecting the life span.The study showed that glucose induced toxicity is rescued by Rifampicin in a worm model of Hyperglycemia. Screening of novel Rifampicin synthesized analogs, led to identification of such analogs that were found to have antiglycating effect and could rescue glucose toxicity to different extent.The study indicates that Rifampicin and its analog have protective role during diabetes without inflicting hepatic damage, and may potentially be considered for repositioning to treat hyperglycemia-related complications in patients.

PHLPP1: A putative target for early Artherosclerosis

The chronic inflammatory disease, atherosclerosis, is the resultant of the accumulation of lipids in the arterial wall. Infiltration of arterial intima by lipid loaded foamy macrophages (foam cells) results in early atherosclerotic lesions, which gradually progress into a necrotic plaque. Despite attempts to gain a comprehensive understanding of foam cell pathways, crucial molecular mechanisms underlying foam cell development are poorly understood. In one such study the investigators explored the functional role of PHLPP1, a Ser/Thr phosphatase in foam cell formation.It was shown that PHLPP1 levels were enhanced in oxidized LDL and endoplasmic reticulum stress (which promotes lipid accumulation) exposed macrophages and HFD-fed zebrafish larvae. 7-ketocholesterol, abundant in atherosclerotic plaques, enhanced PHLPP1 levels through the key lipogenic transcription factor ChREBP. Transcriptomic analysis showed that deficiency of PHLPP1 suppresses gene expression associated with fatty acid synthesis and cholesterol metabolism. Ectopic expression of PHLPP1 augmented cellular cholesterol and free fatty acids levels through the up-regulation of key lipogenic genes such as FASN, CD36 etc. PHLPP1 promoted uptake of OxLDL by macrophages in AMPK/CD36 dependent manner. Interestingly, PHLPP1 interacted with and dephosphorylated ChREBP and enhanced the levels of its target, FASN. Loss of PHLPP1 in zebrafish and C. elegans resulted in reduced High Fat Diet induced lipid accumulation along with decrease in cholesterol and triglyceride levels. Thus, the study suggests that PHLPP1 exerts lipogenic effects through ChREBP/AMPK axis.

Figure: PHLPP1promotes neutral lipid accumulation through AMPK/ChREBP dependent lipid uptake and fatty acid synthesis pathways

BTNL2, a novel T cell coinhibitory molecule, as a therapeutic target in ulcerative colitis

Yet in another project supported on BTNL2, an important immuno-regulatory molecule, as a therapeutic modality in Ulcerative Colitis (UC) murinemodel, the study revealed that the N-terminal ectodomain of BTNL2 (BTNL2 IgV1) alone is able to regulate and inhibit both CD4+ and CD8+ T cell responses and can also delay progression of ulcerative colitis and therefore is a potential therapeutic modality in ulcerative colitis. The three-dimensional structure of BTNL2 IgV1 and structure-guided mutation studies further showed that BTNL2 binds to its putative receptors via a non-canonical binding interface, to inhibit the T cell functions. Importantly, molecular docking and biophysical studies have also demonstrated that BTNL2 shows promiscuous receptor binding.

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